The Coronavirus Exposed. Part 2: Addendum

Table of Contents

-video showing three therapeutics in action

-ventilator associated meds

-medications being currently tested

-With expanded FDA nod, Regeneron’s COVID-19 antibody drug can help the immunocompromised

-Can Ivermectin be used to treat COVID-19 (coronavirus)?

-How antiviral pill molnupiravir shot ahead in the COVID drug hunt

-Will COVID become a disease of the young?


-More information on the vaccines

-How ‘killer’ T cells could boost COVID immunity in face of new variants

-Should you get the Covid-19 vaccine while pregnant?

-Pfizer and Moderna vaccines safe for pregnant people, major study confirms

-The vaccine alternatives for people with compromised immune systems

-The complex situation for immunocompromised people and COVID-19 vaccines

-Why your arm might be sore after getting a vaccine

What we know so far about the effort to vaccinate children

-Why kids need their own COVID-19 vaccine trials

-Yes, vaccines block most transmission of COVID-19

-Future COVID-19 vaccines might not have to be kept so cold

-Why annual COVID-19 boosters may become the norm

-Why vaccine side effects really happen, and when you should worry

-A spritz instead of a jab? Future COVID-19 vaccines may go up your nose.

-Coronavirus in the U.S.: Where cases are growing and declining

-Where can you travel safely once you’ve been vaccinated?

-Will COVID-19 cancel your family reunion?

-Are we there yet? What happens if the U.S. can’t reach herd immunity.

-top 10 reasons to believe the Wuhan Virology Lab caused 2019-nCoV

-covid-19 and healthcare links

Information from The Next Revolution w/Steve Hilton on the Origins of the Coronavirus

-We still don’t know the origins of the coronavirus. Here are 4 scenarios.

-Covid-19 Testing Fiasco Timetable

The origin of COVID: Did people or nature open Pandora’s box at Wuhan?

-What you need to know about the COVID-19 lab-leak hypothesis

-The Delta variant is spreading fast, especially where vaccination rates are low

-The unusual Lambda variant is rapidly spreading in South America. Here’s what we know

-Fact Sheet for Patients And Caregivers, Emergency Use Authorization of ACTEMRA for Coronavirus Disease 2019

-SHAPIRO: Debunking Biden’s COVID Lies

-Delta variant prompts venues to rethink how we stand in line

-Hospital Payments and the COVID-19 Death Count

-CDC, FDA, NIH—what’s the difference?

-The Mu variant is on the rise. Scientists weigh in on how much to worry.

-The epic COVID-19 memorial on the National Mall, in one stunning photo

-Why even fully vaccinated older people are at high risk for severe COVID-19

-How coronavirus compares to flu, Ebola, and other major outbreaks

-How the rise of antivirals may change the course of the pandemic

-Do vaccines protect against long COVID? What the data say

-Heavily mutated coronavirus variant puts scientists on alert

-The Covid Response Has Broken Our Trust in American Institutions

Video showing three therapeutics in action:

This treatment modality could revolutionize the treatment for covid-19. President Trump is the first person to receive it.

*Ventilator use commonly associated medications:

+Sedation: Versed, Fentanyl, Precedex ( notable Heart rate suppression with higher doses), Propofol(should be as a last alternative, blood pressure suppression)

+Proton Pump inhibitors; Pepcid, Protonix

+Blood Pressure Support: phenylephrine, vasopressin, dopamine, levophed, dobutamine and epinephrine. All have side effects. Including shunting of blood supply to the extremities, and gastrointestinal tract. Some are hard on the blood vessels and require special large bore IV’s like PICC lines and central Lines.

+paralytics: are sometimes required to slow down the respiratory rate.


I am not a doctor, I am a nurse with a License that I have to protect. So I have to be very careful what I say, and I can’t make any recommendations, because that would be practicing medicine without a license, something I would never do. But If I had a family member in the hospital with covid I would really want an aggressive doctor. I would ask about hydroxychloroquine, zinc, zithromycin, lovenox, Remdesevir, IVF and decadron as an early treatment. And if your loved one is intubated , ask about dialysis, fentanyl and versed for sedation, no lasix unless patient is a CHF patient, heparin drip for blood clots, more decadron, and convalescent plasma, what can it hurt. Monoclonal Antibodies are coming out. Remember I am not recommending these things, just suggesting that you open up a dialog with your doctor. It pays to be a little educated on the disease and treatments when you talk to them.

Medications that are being currently tested:



Developed a decade ago, this drug failed in clinical trials against Ebola in 2014. But it was found to be generally safe in people. Research with MERS, a disease caused by a different coronavirus, showed that the drug blocked the virus from replicating. The drug is being tested in many COVID-19 clinical trials around the world. This includes studies in which remdesivir is being administered alongside other drugs, such as the anti-inflammatory drug baricitinibTrusted Source. The drug is also being tested in children with moderate to severe COVID-19.

In late April, the drug’s manufacturer, Gilead Sciences, announced one of its trials had been “terminated” due to low enrollment. Gilead officials said the results of that trial had been “inconclusive” when it was ended. A few days later, the company announced that preliminary data from another trial of remdesivir overseen by the National Institute of Allergy and Infectious Diseases (NIAID) had “met its primary endpoint.”

Dr. Anthony FauciTrusted Source, the institute’s director, told reporters the trial produced a “clear cut positive effect in diminishing time to recover.” He said people taking the drug recovered from COVID-19 in 11 days compared with 15 days for people who didn’t take remdesivir. More details will be released after the trial is peer reviewed and published. Gary Schwitzer, founder of, though, said the researchers changed the primary endpoint 2 weeks before Fauci’s announcement.

At the same time, another studyTrusted Source published in The Lancet reported that participants in a clinical trial who took remdesivir showed no benefits compared to people who took a placebo. Despite the conflicting results, the FDA issued an orderTrusted Source on May 1 for the emergency use of remdesivir. In early June, federal officials announced their supply of remdesivir will run out by the end of June. Gilead is ramping up production, but it’s unclear how much of the drug will be available this summer.

In mid-July, Gilead officials announced results from an ongoing phase III trial of remdesivir. They said the drug was “associated with an improvement in clinical recovery and a 62 percent reduction in the risk of mortality compared with standard of care.” They called it an an “important finding that requires confirmation in prospective clinical trials.” In mid-September, officials at Eli Lilly announced that in early stage trials their drug Olumiant when added to remdesivir can shorten hospital stays by one day for people with COVID-19. Olumiant is already used to treat rheumatoid arthritis and other conditions that involved overactive immune systems.


This antiviral was tested along with the drug lopinavir/ritonavir as a treatment for COVID-19. Researchers reported in mid-April that the two drugs didn’t improve the clinical outcomes for people hospitalized with mild to moderate cases of COVID-19.


This drug was created by scientists at a nonprofit biotech company owned by Emory University. Research in mice has shown that it can reduce replication of multiple coronaviruses, including SARS-CoV-2. Pharmaceutical company Merck and Ridgeback Biotherapeutics LP signed an agreement in May to develop this drug. It’s already being tested in a clinical trial in the United Kingdom. Unlike remdesivir, EIDD-2801 can be taken orally, which would make it available to a larger number of people.


This drug is approved in some countries outside the United States to treat influenza. Some reports from China suggest it may work as a treatment for COVID-19. These results, though, haven’t been published yet. Japan, where the medication is made, is sending the drug to 43 countries for clinical trial testing in people with mild or moderate COVID-19. Canadian researchers are testing to see whether the drug can help fight outbreaks in long-term care homes.


This is a combination of two drugs — lopinavir and ritonavir — that work against HIV. Clinical trials are being done to see whether it also works against SARS-CoV-2. One small study published May 4 in the journal Med by Cell Press found that lopinavir/ritonavir didn’t improve outcomes in people with mild or moderate COVID-19 compared to those receiving standard care. Another study, published May 7 in the New England Journal of Medicine, found that the drug combination wasn’t effective for people with severe COVID-19. But another studyTrusted Source found that people who were given lopinavir/ritonavir along with two other drugs — ribavirin and interferon beta-1b — took less time to clear the virus from their body. This study was published May 8 in The Lancet.

Merimepodib (VX-497)

This drug developed by ViralClear Pharmaceuticals Inc. has been shown previously to have antiviral and immune-suppressing effects. It was tested against hepatitis C but had only modest effects. The company is running a phase II trial of this drug. People with advanced COVID-19 will be randomized to receive either merimepodib with remdesivir, or remdesivir plus a placebo. The company hopes to have results by late summer of this year.


REGN-COV2 is a combination of two monoclonal antibodies (REGN10933 and REGN10987) and was designed specifically to block infectivity of SARS-CoV-2, the virus that causes COVID-19.  It appeared to help the seronegative patients, powerfully reducing the amount of virus found in nasopharyngeal swabs and alleviating symptoms more quickly. Both Lilly and Regeneron say they are discussing their data with regulators to see whether their monoclonal antibodies might warrant moving to widespread use more quickly through mechanisms like the U.S. Food and Drug Administration’s emergency use authorization process. Additional studies of their monoclonal treatments are underway in hospitalized COVID-19 patients and, separately, as preventives in uninfected people.

With expanded FDA nod, Regeneron’s COVID-19 antibody drug can help the immunocompromised

Since capturing its initial FDA approval for its COVID-19 antibody drug in November, Regeneron has added nods for subcutaneous injection and a smaller dose. Now comes another endorsement as a preventative treatment. (Regeneron)ShareFacebookTwitterLinkedInEmailPrint

With its rapid mutations, the evolutionary process of the coronavirus makes it a moving target. And so it is with treatments for the disease, which can quickly become in vogue or obsolete.  

Case in point for the former: Regeneron’s antibody cocktail REGEN-COV. Over the last few months, nearly every development in the COVID-19 antibody market has broken in favor of the treatment, a combination of casirivimab and imdevimab.

On Friday, the FDA granted emergency use authorization to REGEN-COV as a preventative measure for those who have been exposed to COVID-19 and who are at high risk to progress to a severe case because they are not fully vaccinated or are not expected to mount an adequate antibody response to vaccination. 

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About 3% of the U.S. population won’t respond fully to COVID-19 vaccines, including patients on chemotherapy, people with hematologic cancers and others, Regeneron says.

The FDA based its decision on a phase 3 trial, run jointly with the National Institutes of Health, which showed that REGEN-COV cut the risk of developing symptomatic COVID by 81% among healthy individuals who lived with an infected person.

The study tested the med in 1,505 people who lived with an infected person within the prior four days. Those who received an infusion of REGEN-COV showed 72% efficacy against symptomatic COVID over the first week and 93% beyond the first week.

Additionally, among those who developed symptoms, REGEN-COV recipients cleared the virus faster than those in the placebo group. 

While vaccine recipients need time to build an effective antibody response, especially with a two-shot regimen, a direct injection of antibodies can offer more immediate protection.  

The FDA granted REGEN-COV its initial EUA in November for patients with newly diagnosed COVID-19 who are at a high risk of progressing to severe disease. Since then, the drug Regeneron’s therapy has gained FDA nods for a subcutaneous injection and at a smaller dose.

Regeneron’s antibody trailed Eli Lilly’s antibody onto the market, but it has since proven more resilient against mutations than its rival. Another antibody drug gained FDA approval two months ago. But sotrovimab, a joint effort from GlaxoSmithKline and Vir Biotechnology, has yet to secure a supply deal from the United States.

Can Ivermectin be used to treat COVID-19 (coronavirus)?

Can Ivermectin be used to treat COVID-19 (coronavirus)?

Official Answer


  • Ivermectin should only be used in patients for COVID-19 in a research setting, as part of a clinical trial.
  • An in vitro trial has shown ivermectin reduces the number of cell-associated viral RNA by 99.8 % in 24 hours. An in vitro study is when they study cells in a laboratory and not in a living organism.
  • Clinical trials have been conducted on people to test how well ivermectin works against COVID-19. This is in vivo testing. Currently there is a low level of certainty whether ivermectin helps treat COVID-19 and more studies are needed.
  • Ivermectin tablets are currently a FDA approved medicine for treatment of intestinal worms, Strongyloides stercoralis and Onchocerca volvulus.
  • It has been established as safe for human use.
  • SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) is the virus that causes COVID-19 (coronavirus disease 2019)

What is Ivermectin?

  • Ivermectin is a medicine currently used to treat parasite infections such as intestinal worms, lice and mites.
  • Recently ivermectin has also been studied to treat a range of viruses.

How is Ivermectin thought to work on COVID-19?

  • For the SARS-CoV-2 virus to make you sick, it has to first infect your cells.
  • Then while inside the cell, the virus makes heaps of copies of itself, so it can spread around your body.
  • The virus also has ways of reducing the way your body fights the infection.
  • During the infection of the cell, some viral proteins go into the cell nucleus, and from here they can decrease the body’s ability to fight the virus, which means the infection can get worse.
  • To get into the nucleus the viral proteins need to bind a cargo transporter which lets them in.
  • Ivermectin can block the cargo transporter, so the viral proteins can’t get into the nucleus. This is how the scientists believe Ivermectin works against SARS-CoV-2 virus.
  • By taking Ivermectin, it means the body can fight the infection like normal, because its antiviral response hasn’t been reduced by the viral proteins.

Is Ivermectin an approved medicine by the FDA?

Ivermectin tablets (Stromectol) are an approved by the FDA for use in intestinal worms Strongyloides stercoralis and Onchocerca volvulus.

Ivermectin cream 1% (Soolantra) is FDA approved for rosacea.

Ivermectin is not FDA approved to treat COVID-19.

Ivermectin tablets are also used off-label for a number of other conditions.

Ivermectin intended for animal use should not be taken by humans.

The WHO Therapeutics and COVID-19 living guideline: Ivermectin

The WHO Therapeutics and COVID-19 living guideline is the World Health Organization’s (WHO) most up-to-date recommendations of treatments of COVID-19.

Their recommendation is that ivermectin should not used in patients with COVID-19 unless it is in a research setting, as part of a clinical trial.

This recommendation is the result of a systematic review of randomised clinical trials that used ivermectin for COVID-19. After analysing the information from these studies, they believe that there is a high degree of uncertainty on whether ivermectin is helpful or harmful in treating COVID-19.

The uncertainty in some of the ivermectin trials for COVID-19 is due to

  • serious risk of bias
  • serious risk of imprecision.

There are far fewer randomized controlled trials (RCT) for ivermectin compared to other COVID treatments. The RCT included multiple small trials, that had fewer patients enrolled and had fewer events recorded.

More RCT are needed with higher quality of evidence to determine if ivermectin is successful at treating COVID-19.

ICON Clinical Study Results

(Use of Ivermectin Is Associated With Lower Mortality in Hospitalized Patients With Coronavirus Disease 2019: The Ivermectin in COVID Nineteen Study)

The ICON study, which was a multihospital retrospective cohort study, involved 280 patients, 173 patients were treated with at least one oral dose of 200 μg/kg ivermectin and 107 patients had no ivermectin treatment. Patients could also be treated with hydroxychloroquine, azithromycin, or both.

The results from this study showed that:

  • Overall mortality was significantly lower for the ivermectin group (15%) compared to the usual treatment group (25.2%) using figures from the unmatched cohort.
  • Mortality for the subgroup of patients who had severe pulmonary involvement was lower in the ivermectin treatment group (38.8%) compared to the usual treatment group (80.7%) from the unmatched cohort.
  • There was no significant difference between the two treatment groups regarding successful extubation rates of mechanically ventilated patients. Successful extubation is when the patient has had the breathing tube that has been used for mechanical ventilation removed and they can successfully breath on their own.
  • Length of hospital stay was not significantly different between the ivermectin treatment group and the regular treatment group.

For secondary analysis of the results propensity score matching was performed, which is when the researcher matches a person in the treatment group to a person in the non-treatment group who has similar characteristics. This reduces the effects of confounding and selection bias.

  • For the propensity matched cohort figures the mortality was significantly lower in the ivermectin treatment group compared to the regular treatment group (13.3% vs 24.5%; odds ratio, 0.47; 95% confidence interval, 0.22-0.99; P < .05).

The study noted that “Interpretation of these findings are tempered by the limitations of the retrospective design and the possibility of confounding” and that “Further studies in appropriately designed randomized trials are recommended before any conclusions can be made.”

There has been feedback in regard to this study querying some of the important variables and how they may have affected the study outcome.


Ivermectin to prevent hospitalizations in patients with COVID-19 (IVERCOR-COVID19) a randomized, double-blind, placebo-controlled trial

The IVERCOR-COVID-19 trial was a randomized, double-blind, placebo controlled trial involving 501 patients. The aim of this trial was to determine whether ivermectin treatment could prevent hospitalization of individuals with early COVID-19. One group was treated with ivermectin plus standard treatment and the other group was treated with placebo with standard treatment. Patients were not allowed to take hydroxychloroquine, chloroquine or antiviral drugs.

The results of this trial were published on 2 July 2021 showed that:

  • The percentage of patients that needed hospitalization was 5.6% in the ivermectin treatment group and 8.4% in the placebo group, but the difference between the two groups was not statistically significantly
  • There was no statistically significant difference in median time from patient enrollment to hospitalization between the treatment groups. The ivermectin treatment group median time to hospitalization was 3.5 days and placebo group 3 days.
  • There was no statistically significant difference in mean time from study enrolment until a patient was put on invasive mechanical ventilatory support (MVS). The ivermectin treatment group was 5.25 days compared to the placebo group which was 10 days.

The limitations in this study was noted as a:

  • low percentage of hospitalized patients
  • The mean dose of ivermectin was 192.37  μg/kg/day which was below the dose proposed as probably being effective.


Platform Randomised Trial of Treatments in the Community for Epidemic and Pandemic Illnesses (PRINCIPLE)

The PRINCIPLE trial is a current trial investigating treatments for COVID-19 patients in the community who are more at risk of serious illness. The study is investigating a number of different treatments including ivermectin.

Participants in the ivermectin part of the trial will be:

  • Between the age 18 and 64 years old
  • With a underlying health condition or shortness of breath due to COVID-19
  • Must join trial within first 14 days of covid-19 symptoms or a positive test
  • Will be assigned to receive 3 day course of oral ivermectin treatment
  • They will be compared to a group of patients receiving standard NHS COVID-19 care.

The ivermectin part of this trial started in June 2021 and results will be published when available.

What happens next?

We will be waiting for the results of more clinical trials in patients to see how well ivermectin works in treating COVID-19.

The randomized clinical trials need to have a high quality of evidence, without the limitations of risk of bias, imprecision, inconsistency between studies, and indirectness of publication bias.

As Ivermectin is already a FDA approved medicine we already know that it has been established as safe for human use when used at the standard dose.

Related Information: COVID-19: Prevention & Investigational Treatments

Bottom line

  • Ivermectin should not be used in patients for COVID-19, unless it is part of a clinical trial.
  • Currently there is not enough high quality evidence supporting the use of ivermectin for COVID-19 treatment.
  • More randomized clinical trials with a higher certainty of evidence are needed for ivermectin in the treatment COVID-19.
  • Ivermectin tablets are FDA approved medicine for some types of intestinal worms and ivermectin cream is FDA approved for rosacea treatment.
  • Both oral and topical ivermectin have a good safety profile at standard dosing levels.

How antiviral pill molnupiravir shot ahead in the COVID drug hunt

The Merck pill, which could become the first oral antiviral COVID treatment, forces the SARS-CoV-2 coronavirus to mutate itself to death.

(Update 10/11/2021)

The pharmaceutical firm Merck announced last week that an antiviral pill it’s developing can cut hospitalizations and deaths among people with COVID-19 by half. The results haven’t yet been peer reviewed. But if the drug candidate, molnupiravir, is authorized by regulators, it would be the first oral antiviral treatment for COVID-19. By contrast, the other currently authorized drugs must be delivered intravenously or injected.

A pill could make treating patients earlier on in their infection much easier — and more effective. It could also keep hospitals from overflowing, especially in places where vaccination rates are still low, such as many low- and lower-middle-income countries. Molnupiravir was so effective in a phase 3 trial involving COVID-19-positive people at risk of severe illness that clinicians halted enrolment early.

But whether this clinical-trial success story will translate into a global game-changer in the fight against the pandemic isn’t yet clear. Even if lower-income countries can afford the medicine, they might not have the diagnostic capacity to treat patients with molnupiravir early in the course of their illness, when treatment could make a difference.

This week, two Indian drugmakers independently testing generic molnupiravir in people with moderate illness due to COVID-19 sought to end their trials because they saw no “significant efficacy” for the experimental drug, although they plan to continue trials for people with mild illness. Merck’s findings, which were disclosed in a press release and have yet to be pored over by scientists and submitted to regulators for approval, applied to people with mild-to-moderate cases of COVID-19 who were not hospitalized. A spokesperson for Merck points out that moderate COVID-19 cases in India are defined as being more severe than in the United States and involve hospitalization.

Hit early, hit hard

The other therapies on offer against COVID-19, Gilead Science’s antiviral remdesivir and a monoclonal antibody cocktail from biotech firm Regeneron, must be administered intravenously or by injection. That makes it difficult for people to access the therapies before they are sick enough to land in hospital. And remdesivir is approved only for those who are already hospitalized with COVID-19.

Yet it’s better to “hit early, hit hard” with antivirals, says Richard Plemper, a virologist at Georgia State University in Atlanta. The sicker the patient, the less effective the drugs are at treating the illness. A COVID-19 pill, which simply requires a prescription and a trip to the pharmacy once symptoms appear, would make early treatment much easier.

COVID-19 is not the first disease caused by a coronavirus to seriously impact humans. But the 2002–04 severe acute respiratory syndrome (SARS) epidemic fizzled out quickly, and the Middle East respiratory syndrome (MERS) outbreak in 2012 never became widespread — meaning that drugmakers had little incentive to develop antivirals against these diseases.

So when the first cases of COVID-19 emerged in late 2019, “there wasn’t a portfolio of antivirals waiting”, says Saye Khoo, an infectious-disease physician at the University of Liverpool, UK, who has led a clinical trial of molnupiravir.

Initial efforts to find treatments focused on drugs already approved by regulators, and yielded only one winner: dexamethasone, a steroid aimed at dampening an overblown inflammatory response in the sickest people. The FDA has not authorized the drug for this purpose, but it’s widely used to treat the sickest people.

A nurse treats a patient with Remdesivir in hospital
The US Food and Drug Administration has authorized remdesivir, an intravenously administered antiviral, only for use in people hospitalized with COVID-19.Credit: Scott Olson/Getty

But even as researchers scrambled to test approved drugs, pharmaceutical companies and biotechnology firms were scouring their libraries for any compounds with known antiviral activity that might stop the SARS-CoV-2 coronavirus. These broad-acting antivirals weren’t designed specifically to target SARS-CoV-2, but it seemed mechanistically feasible that they could. Unlike with many of the drugs tested early in the pandemic, “there’s a scientific rationale. You understand how they’re working”, says Jay Luly, chief executive of Enanta Pharmaceuticals, a company in Watertown, Massachusetts, that is developing its own COVID-19 antiviral.

So far, Gilead’s remdesivir is the only such drug that has received approval from the US Food and Drug Administration. When used in a hospital setting, its effect is modest. In a phase 3 trial, researchers found that it shortened recovery time by a median of 5 days. Merck hopes molnupiravir will be next to receive authorization.

Hot pursuit

Molnupiravir began as a possible therapy for Venezuelan equine encephalitis virus at Emory University’s non-profit company DRIVE (Drug Innovation Ventures at Emory) in Atlanta. But in 2015, DRIVE’s chief executive George Painter offered it to a collaborator, virologist Mark Denison at Vanderbilt University in Nashville, Tennessee, to test against coronaviruses. “I was pretty blown away by it,” Denison remembers. He found that it worked against multiple coronaviruses: MERS and mouse hepatitis virus.

Painter also recruited his collaborator Plemper to test the drug against influenza and respiratory syncytial virus. After the pandemic hit, however, plans changed. DRIVE licensed the compound to Ridgeback Biotherapeutics in Miami, Florida. Plemper, too, pivoted to coronaviruses, and tested the compound in ferrets. It silenced the virus’s ability to replicate, he says, but it also suppressed the virus’s transmission from infected ferrets to uninfected ones. Merck’s data hint that might also be true in humans: molnupiravir appeared to shorten the duration of SARS-CoV-2’s infectivity in trial participants with the virus.

Molnupiravir, like remdesivir, is a nucleoside analogue, which means it mimics some of the building blocks of RNA. But the compounds work in entirely different ways. When SARS-CoV-2 enters a cell, the virus needs to duplicate its RNA genome to form new viruses. Remdesivir is a ‘chain terminator’. It stops the enzyme that builds these RNA ‘chains’ from adding further links. Molnupiravir, on the other hand, gets incorporated into burgeoning RNA strands and, once inside, wreaks havoc. The compound can shift its configuration, sometimes mimicking the nucleoside cytidine and sometimes mimicking uridine. Those RNA strands become faulty blueprints for the next round of viral genomes. Anywhere the compound gets inserted and that conformational shift happens, a point mutation occurs, Plemper says. When enough mutations accumulate, the viral population collapses. “That is what we term lethal mutagenesis,” he adds. “The virus essentially mutates itself to death.” And because the mutations accumulate randomly, it’s difficult for viruses to evolve resistance to molnupiravir — another plus for the compound.

But the compound’s mutagenic potential in human cells — the possibility that it could incorporate itself into DNA — does raise safety concerns, some researchers say. Merck hasn’t released any detailed safety data yet, but “we’re very comfortable that the drug will be safe if used as intended”, said Daria Hazuda, Merck’s vice-president of infectious-disease discovery and chief science officer, at a press briefing last Friday.

Waiting in the wings

Other antivirals are in the works. Gilead Sciences is developing a pill version of remdesivir. And Denison suspects that if the antiviral were given to people as early as molnupiravir is — when symptoms have only just appeared and viral loads are high — it would be similarly effective. In a study presented at IDWeek, a virtual meeting of infectious-disease specialists and epidemiologists held earlier this month, researchers reported results of administering infusions of remdesivir to people in the early stages of COVID-19 every day for three days. The number of participants in the study was small, but remdesivir appeared to reduce hospitalizations by 87% in people at high risk of developing COVID-19.

Biotech firm Atea Pharmaceuticals in Boston, Massachusetts, also has an antiviral in the works. It was testing a nucleoside analogue against hepatitis C in a clinical study when SARS-CoV-2 emerged. The pandemic paused the trial, so Atea decided to switch its focus to COVID-19. Now it has partnered with Roche in Basel, Switzerland, to develop its compound.

Pfizer, based in New York City, had a bit of a head start too. The company had been developing antivirals against SARS since the early 2000s, but shelved them when the outbreak ebbed. When the COVID-19 pandemic began, “they just blew the dust off”, Luly says. Researchers are currently testing a pill form of a compound that has a mechanism of action similar to those original versions. It is in phase 2/3 trials for treating people who are newly infected.

Global access

An effective oral antiviral would be an incredible asset in the fight against COVID-19, but it’s not yet clear whether molnupiravir will be accessible to all. “Are we going to be in a situation where the price is reasonable in low- and middle-income countries?” asks Rachel Cohen, the North American executive director at the Drugs for Neglected Diseases initiative.

The United States has agreed to purchase 1.7 million courses of molnupiravir for US$1.2 billion, which works out to about $700 per 5-day course. That’s far less than the price of remdesivir or monoclonal antibodies, but still too costly for much of the world. Merck, which is co-developing the compound with Ridgeback, has struck licensing agreements with five Indian manufacturers of generic drugs. Those deals allow the manufacturers to set their own price in India and 100 other low- and lower-middle-income countries.

But even if poorer countries can afford the drug, they might not have the diagnostic capacity to use it properly. If molnupiravir needs to be given in the first five days after symptom onset, “that requires that we are able to actually rapidly diagnose people”, Cohen says. For many developing countries — and even some wealthy ones — “that is actually a huge challenge”.

Will COVID become a disease of the young?

A growing share of infections among unvaccinated youths in countries with high vaccination rates is putting the spotlight on the role of young people in the pandemic.

On 21 June, Israel’s Ministry of Health recommended that all individuals aged 12–15 be vaccinated against COVID-19 — making the nation one of the few that have so far approved vaccinations for younger adolescents. The decision came in response to a trend that many countries with high rates of vaccination are experiencing: an ever-increasing proportion of new infections are in younger age groups (see ‘Trending younger’).

Israel’s swift vaccination campaign — which has now reached more than 85% of the adult population — saw case numbers drop to around a dozen a day in early June. But later that month, cases began to rise to more than 100 a day, many of in people under 16, leading the government to open up vaccinations to all teenagers.

The younger profile of cases is not surprising, says Ran Balicer, an epidemiologist at Israel’s largest health-care provider, Clalit Health Services, in Tel Aviv. But it highlights the possibility that subsequent waves of community spread could be driven by younger age groups, especially in the presence of new, more transmissible variants.

Growing trend globally

It’s a trend that’s not restricted to Israel. In the United States and the United Kingdom, COVID-19 has “become a disease of the unvaccinated, who are predominantly young”, says Joshua Goldstein, a demographer at the University of California, Berkeley.

This shift is occurring in many countries that vaccinated older people first, and are now reaching high levels of vaccination in the adult population. It follows an earlier drop in age resulting from public-health measures to prevent the spread of COVID-19 among older people who are most at risk of severe disease, such as those in nursing homes, say researchers.

And the shift has brought fresh impetus to studies of transmission and disease in younger age groups. To make better policy decisions, “it’s becoming more and more important to understand the burden of disease among children and adolescents”, says Karin Magnusson, an epidemiologist at the Norwegian Institute of Public Health in Oslo.

Magnusson has looked at the impact of COVID-19 in children on Norway’s health-care system. In a 5 June preprint1, she reported that although they didn’t need specialist care, children often needed to see their doctor repeatedly for up to six months after contracting the virus.

Balicer is studying viral spread in multigenerational households in Israel. Beyond decisions about vaccinating children, the changing patterns of COVID-19 infection have also fuelled discussions about extending health measures such as mask wearing to adolescents and kids in Israel, he says.

Proportional not absolute increase

“As the burden of cases shifts towards younger people, arguments for vaccinating adolescents will become slightly more compelling,” agrees Nick Bundle, an epidemiologist at the European Centre for Disease Prevention and Control in Stockholm. However, the overall risk of severe disease in children remains low, and in many countries that have observed the proportion of cases rising in younger age groups, the total number of cases has fallen, he points out.

And countries also need to consider the global context, say researchers. “Are we really better off giving the vaccine to kids in rich countries than to older people [in less wealthy countries] where it might have a much bigger impact on people’s lives?” says Jennie Lavine, who studies infectious-disease dynamics at Emory University in Atlanta, Georgia. “It seems hard for me to imagine a really good argument for that.”

Although the downward shift in the average age of infections in countries with high COVID-19 vaccination rates is an interesting phenomenon, it might be short-lived, say some researchers. A few scenarios could shift the balance back, says Henrik Salje, an infectious-disease epidemiologist at the University of Cambridge, UK. Many countries could start to vaccinate younger people — as Israel and the United States are already doing — or new variants and waning immunity among older age groups could make them freshly susceptible, he says.

COVID-19 could still become a disease of the young, says Bundle. “But how big a problem that is, is not a simple thing to respond to.”


Biologically, a vaccine against the COVID-19 virus is unlikely to offer complete protection. Logistically, manufacturers will have to make hundreds of millions of doses while relying, perhaps, on technology never before used in vaccines and competing for basic supplies such as glass vials. Then the federal government will have to allocate doses, perhaps through a patchwork of state and local health departments with no existing infrastructure for vaccinating adults at scale. The Centers for Disease Control and Prevention, which has led vaccine distribution efforts in the past, has been strikingly absent in discussions so far—a worrying sign that the leadership failures that have characterized the American pandemic could also hamper this process. To complicate it all, 20 percent of Americans already say they will refuse to get a COVID-19 vaccine, and with another 31 percent unsure, reaching herd immunity could be that much more difficult.

The good news, because it is worth saying, is that experts think there will be a COVID-19 vaccine. The virus that causes COVID-19 does not seem to be an outlier like HIV. Scientists have gone from discovery of the virus to more than 165 candidate vaccines in record time, with 27 vaccines already in human trials. Human trials consist of at least three phases: Phase 1 for safety, Phase 2 for efficacy and dosing, and Phase 3 for efficacy in a huge group of tens of thousands of people. At least six COVID-19 vaccines are in or about to enter Phase 3 trials, which will take several more months.

We are almost five months into the pandemic and probably another five from a safe and effective vaccine—assuming the clinical trials work out perfectly. “Even when a vaccine is introduced,” says Jesse Goodman, the former chief scientist at the Food and Drug Administration, “I think we will have several months of significant infection or at least risk of infection to look forward to.”

All of this means that we may have to endure more months under the threat of the coronavirus than we have already survived. Without the measures that have beat back the virus in much of Europe and Asia, there will continue to be more outbreaks, more school closings, more loneliness, more deaths ahead. A vaccine, when it is available, will mark only the beginning of a long, slow ramp down. And how long that ramp down takes will depend on the efficacy of a vaccine, the success in delivering hundreds of millions of doses, and the willingness of people to get it at all. It is awful to contemplate the suffering still ahead. It is easier to think about the promise of a vaccine.

Vaccines are, in essence, a way to activate the immune system without disease. They can be made with weakened viruses, inactivated viruses, the proteins from a virus, a viral protein grafted onto an innocuous virus, or even just the mRNA that encodes a viral protein. Getting exposed to a vaccine is a bit like having survived the disease once, without the drawbacks. A lot remains unknown about the long-term immune response to COVID-19, but, as my colleague Derek Thompson has explained, there are good reasons to believe getting COVID-19 will protect against future infections in some way. Vaccine-induced immunity, though, tends to be weaker than immunity that arises after an infection. Vaccines are typically given as a shot straight into a muscle. Once your body recognizes the foreign invader, it mounts an immune response by, for example, producing long-lasting antibodies that circulate in the blood.

Even if all of this goes well—the earliest candidates are effective, the trials conclude quickly, the technology works—another huge task lies ahead: When vaccines are approved, 300 million doses will not be available all at once, and a system is needed to distribute limited supplies to the public. This is exactly the sort of challenge that the U.S. government has proved unprepared for in this pandemic.

I have an update on Vaccinations There are currently three vaccines that have either have finished stage three or are almost finished this level of testing. Pfizer is the first to its vaccine get it approved by England. It is currently being evaluated by our rather sluggish FDA. It has proven to be safe in all ages and is rated at 95% effective, though it likely will take two injections. Moderna has come out with a vaccine, that will soon be evaluated by the FDA as well, it is also 94 to 95% effective, though it requires less stringent storage facilities, which should help its administration in more rural, areas. The third company, AstraZeneca is still in its last stage of trials, it has had a little road block with dosing, but it is being touted as be just as effective and cheaper and even easier to store than Moderna’s vaccine. While the first two should be rolled out this year, it may take a few months longer for the third one. In 2021, we should see even more vaccines rolling out, which will help increase the inoculation rate world wide. In the U.S. first responders and the elderly and higher risk individuals will get the vaccination first, the general population will start receiving the vaccinations around May or June of 2021. (update 12/5/2020)

More Information on the Vaccines

How Bureaucracy Killed Hundreds of Thousands of Americans

Over the course of the COVID-19 pandemic, the media have spilled barrels of ink over mistakes by the federal government. We’ve heard endlessly about the failure to quickly ramp up testing, the confusion over mask-wearing and the debates over proper lockdown policy. But when the history of this time is written, the fundamental mistake made by the United States government won’t be rhetorical excesses by the president or conflicting public health advice. It will be the same mistake the government always makes: trusting the bureaucracy.

We now know that the miraculous Moderna vaccine for COVID-19 had been designed by Jan. 13, 2020 . That was just two days after the sequencing of the virus had been made public. As David Wallace-Wells writes for New York magazine, “the Moderna vaccine design took all of one weekend. … By the time the first American death was announced a month later, the vaccine had already been manufactured and shipped to the National Institutes of Health for the beginning of its Phase I clinical trial.” Meanwhile, for six weeks, Dr. Anthony Fauci assured Americans that there was little to worry about with COVID-19.

Fast-forward to the end of 2020. Hundreds of thousands of Americans have died. Tens of thousands of Americans continue to die every week. The Food and Drug Administration has still not cleared the Oxford-AstraZeneca vaccine, which costs a fraction of the other vaccines (about $4 per dose, as opposed to $15 to $25 per dose for Moderna’s vaccine or $20 per dose for the Pfizer-BioNTech vaccine). The FDA approval process cost us critical months, with thousands of Americans dying each day. As Dr. Marty Makary of Johns Hopkins University told me this week, “Safety is their eternal excuse. They are entirely a broken federal bureaucracy … Why did we not have a combined Phase I-Phase II clinical trial for these vaccines?”This is an excellent question, of course. Phase I trials involve small numbers of participants, who are then monitored. Phase II trials involve larger numbers. Huge numbers of Americans would have volunteered for a combined Phase I-Phase II trial. And even after we knew the vaccines were effective, the FDA delayed. Data was collected by late October that suggested Phase II/III trials had been successful. The FDA quickly requested more results, which it did not receive until November. It then took until Dec. 11 for the FDA to issue emergency use authorization for the Pfizer vaccine. The Moderna vaccine wasn’t cleared until Dec. 18, nearly a year after it had first been produced.

The disgrace continues. The government continues to hold back secondary doses of the vaccine, despite the fact that the first doses provide a significant effect. As Makary says, “We’re in a war. The first dose gives immunity that may be as high as 80 to 90 percent protection, and we can probably give half the dose, as Dr. Moncef Slaoui suggested … We can quadruple our supply overnight.”

Meanwhile, states continue to be confused by the Centers for Disease Control and Prevention guidance on how to tranche out the vaccines. It took until nine days after the FDA authorized the Pfizer vaccine for the CDC to release its recommendations. Those recommendations were still complex and confusing and often rife with self-defeating standards — even though it was perfectly obvious from the start that the solution ought to be based on age.

Americans have relied on the government — a government supposedly comprised of well-meaning experts — to get us through a pandemic. The government not only failed with conflicting information and incoherent lockdown policy but also actively obstructed the chief mechanism for ending the pandemic thanks to bureaucratic bloat. If Americans’ takeaway from the COVID-19 pandemic is that centralized government is the all-purpose solution, they’re taking precisely the lesson most likely to end in mass death in the future. (Updated 1/12/2021)

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Supersites for getting the Vaccination in the US. (Updated 2/28/2021)

The website listed below is a good starting place to gain information on where to find locations for getting the vaccination.

How ‘killer’ T cells could boost COVID immunity in face of new variants

(Updated 2/15/2021)

In the race against emerging coronavirus variants, researchers are looking beyond antibodies for clues to lasting protection from COVID-19.

Concerns about coronavirus variants that might be partially resistant to antibody defences have spurred renewed interest in other immune responses that protect against viruses. In particular, scientists are hopeful that T cells — a group of immune cells that can target and destroy virus-infected cells — could provide some immunity to COVID-19, even if antibodies become less effective at fighting the disease.

Researchers are now picking apart the available data, looking for signs that T cells could help to maintain lasting immunity.

“We know the antibodies are likely less effective, but maybe the T cells can save us,” says Daina Graybosch, a biotechnology analyst at investment bank SVB Leerink in New York City. “It makes sense biologically. We don’t have the data, but we can hope.”

Coronavirus vaccine development has largely focused on antibodies, and for good reason, says immunologist Alessandro Sette at the La Jolla Institute for Immunology in California. Antibodies — particularly those that bind to crucial viral proteins and block infection — can hold the key to ‘sterilizing immunity’, which not only reduces the severity of an illness, but prevents infection altogether.

That level of protection is considered the gold standard, but typically it requires large numbers of antibodies, says Sette. “That is great if that can be achieved, but it’s not necessarily always the case,” he says.

Killer cells

Alongside antibodies, the immune system produces a battalion of T cells that can target viruses. Some of these, known as killer T cells (or CD8+ T cells), seek out and destroy cells that are infected with the virus. Others, called helper T cells (or CD4+ T cells) are important for various immune functions, including stimulating the production of antibodies and killer T cells.

T cells do not prevent infection, because they kick into action only after a virus has infiltrated the body. But they are important for clearing an infection that has already started. In the case of COVID-19, killer T cells could mean the difference between a mild infection and a severe one that requires hospital treatment, says Annika Karlsson, an immunologist at the Karolinska Institute in Stockholm. “If they are able to kill the virus-infected cells before they spread from the upper respiratory tract, it will influence how sick you feel,” she says. They could also reduce transmission by restricting the amount of virus circulating in an infected person, meaning that the person sheds fewer virus particles into the community.

T cells could also be more resistant than antibodies to threats posed by emerging variants. Studies by Sette and his colleagues have shown that people who have been infected with SARS-CoV-2 typically generate T cells that target at least 15–20 different fragments of coronavirus proteins1. But which protein snippets are used as targets can vary widely from person to person, meaning that a population will generate a large variety of T cells that could snare a virus. “That makes it very hard for the virus to mutate to escape cell recognition,” says Sette, “unlike the situation for antibodies.”

So when laboratory tests showed that the 501Y.V2 variant identified in South Africa (also called B.1.351) is partially resistant to antibodies raised against previous coronavirus variants, researchers wondered whether T cells could be less vulnerable to its mutations.

Early results suggest that this might be the case. In a preprint published on 9 February, researchers found that most T-cell responses to coronavirus vaccination or previous infection do not target regions that were mutated in two recently discovered variants, including 501Y.V22. Sette says that his group also has preliminary evidence that the vast majority of T-cell responses are unlikely to be affected by the mutations.

If T cells remain active against the 501Y.V2 variant, they might protect against severe disease, says immunologist John Wherry at the University of Pennsylvania in Philadelphia. But it is hard to know from the data available thus far, he cautions. “We’re trying to infer a lot of scientific and mechanistic information from data that doesn’t really have it to give,” he says. “We’re kind of putting things together and building a bridge across these big gaps.”

Updating vaccines

Researchers have been analysing clinical-trial data for several coronavirus vaccines, to look for clues as to whether their effectiveness fades in the face of the 501Y.V2 variant. So far, at least three vaccines — a protein vaccine made by Novavax of Gaithersburg, Maryland, a single-shot vaccine made by Johnson & Johnson of New Brunswick, New Jersey, and a vaccine made by AstraZeneca of Cambridge, UK, and the University of Oxford, UK — were less effective at protecting against mild COVID-19 in South Africa, where the 501Y.V2 variant dominates, than in countries where that variant is less common.

In the case of AstraZeneca’s vaccine, the results were particularly striking: the vaccine was only 22% effective against mild COVID-19 in a sample of 2,000 people in South Africa. However, that trial was too small and its participants too young for researchers to draw any conclusions about severe disease, says Shane Crotty, an immunologist at the La Jolla Institute for Immunology.

Some coronavirus vaccine developers are already looking at ways to develop next-generation vaccines that stimulate T cells more effectively. Antibodies detect only proteins outside cells, and many coronavirus vaccines target a protein called spike that decorates the surface of the virus. But the spike protein is “quite variable”, suggesting that it might be prone to mutating, says Karlsson, and raising the risk that emerging variants will be able to evade antibody detection.

T cells, by contrast, can target viral proteins expressed inside infected cells, and some of those proteins are very stable, she says. This raises the possibility of designing vaccines against proteins that mutate less frequently than spike, and incorporating targets from multiple proteins into one vaccine.

Biotechnology firm Gritstone Oncology of Emeryville, California, is designing an experimental vaccine that incorporates the genetic code for fragments of several coronavirus proteins known to elicit T-cell responses, as well as for the full spike protein, to ensure that antibody responses are robust. Clinical trials are due to start in the first quarter of this year.

But Gritstone president Andrew Allen hopes that current vaccines will be effective against new variants, and that his company’s vaccine will never be needed. “We developed this absolutely to prepare for bad scenarios,” he says. “We’re half hoping that everything we did was a waste of time. But it’s good to be ready.”

Should you get the Covid-19 vaccine while pregnant?

(Updated 2/6/2021)

Pregnant people might hesitate to get vaccinated because there’s no data on how it works for them. Medical experts lay out what is known and how each person can weigh their own risks and benefits.

For people who are pregnant, the rollout of COVID-19 vaccines is prompting agonizing questions about whether it’s safer to get the vaccine or risk infection. Despite emerging evidence that the vaccines are generally safe and effective, there is virtually no data as to whether that’s true for those who are expecting, even though they are at higher risk of complications from the disease.

The world’s regulatory bodies have at times issued contradictory advice about pregnancy and COVID-19 vaccines. The Centers for Disease Control and Prevention (CDC) has said that the vaccines should be available to pregnant people but ultimately leaves the decision up to expectant parents and their doctors. The World Health Organization (WHO) recommends against it unless the pregnant person is at high risk.

So how does someone make an evidence-based decision about whether it’s safe to get the vaccine in the absence of any safety data? “It all turns on the features of your life,” says Ruth Faden, founder of the Johns Hopkins Berman Institute of Bioethics in Maryland. Each person must balance what is known about the vaccine with what is known about their own risk of getting infected.

Although experts suggest talking throughthese decisions with a medical provider, here’s a look at the facts available, what’s still being sorted out, and why there’s reason to be optimistic.

What we know about past vaccines

Scientists generally know quite a lot about vaccines and pregnancy—although historically it has taken longer to get that evidence than general safety data. Because of the ethical complexities of pregnancy—in which parents and their fetuses face interconnected risks—and fears of legal liability, pregnant people are typically excluded from the randomized clinical trials that are required to obtain approval for a drug or vaccine.

In the past, it has taken years after vaccines are approved for general use to gather enough data to show how they work during pregnancy. Many of these follow-on studies are observational and involve fewer participants. As a result, women who are pregnant may be hesitant to get a vaccine, and doctors may hold off on recommending them.

“What has resulted from this has been decades of essentially unfairness to pregnant women,” says Faden, who also leads the Pregnancy Research Ethics for Vaccines, Epidemics, and New Technologies (PREVENT) project. Although at times it might make sense to not include expectant parents in early trials, she says, “we’ve been protecting pregnant women to death.”

But scientists have accumulated incontrovertible evidence that certain vaccines are safe, effective and, in some cases, direly needed. Today, the CDC highly encourages pregnant people to get vaccinations against influenza, which is known to cause severe complications in pregnant women. Medical experts also advise getting the vaccine for pertussis (or whooping cough), which can be fatal to newborns. Expectant people can also receive immunizations for a handful of other diseases, including hepatitis and meningitis.

Lessons from those vaccines have shown that there’s no reason to worry about the types of shots that use an inactivated virus to elicit an immune response, since they cannot infect either the parent or the baby, says Geeta Swamy, associate professor of obstetrics and gynecology at the Duke University School of Medicine in North Carolina and a leading maternal immunization researcher.

On the other hand, vaccines using a small amount of live virus—such as the one for measles, mumps, and rubella and the one for chickenpox—can cause low-grade infections that some scientists worry could harm a fetus. But, Swamy says, “even that is based on theoretical risk concerns,” not on evidence that it occurs.

What’s different about the COVID-19 vaccines

The Moderna and Pfizer-BioNTech vaccines for COVID-19 pose a new challenge. Until now, the messenger RNA platform they use had not been licensed for human use. As such, the only pregnancy-related data available are from preclinical studies in laboratory animals and a handful of clinical trial participants who later discovered they were pregnant. 

But we do know a fair amount about how the mRNA technology works. Instead of using inactivated or live virus, these vaccines contain snippets of genetic code encased in lipids, or fat globules, that protect the code from degrading. Once injected, the mRNA instructs cells to produce the SARS-CoV-2 spike protein, which triggers the body’s immune response.

Theoretically, all of this is promising because, like past vaccines, it does not involve a live virus. “Everything that is understood to be biologically the case about mRNA vaccines is incredibly reassuring,” Faden says. “It shouldn’t have any impact on pregnancy or pregnancy outcomes.”

Anthony Fauci, White House chief medical adviser, has also said that the data “so far has no red flags” for pregnant people.

Still, scientists have raised questions about how the mRNA vaccines will work in reality. The biggest concern is whether mRNA can cross the placenta and generate the spike protein in the fetus. It wouldn’t necessarily be harmful if it did—and would not cause birth defects—but the worry is that the fetus could experience side effects including pain, swelling, and fever. Swamy says the animal studies showed no signs of physical side effects, but that is yet to be tested in humans.

Side effects in the mother may also be an issue. Christina Chambers, a perinatal epidemiologist at the University of California, San Diego, is conducting a study of COVID-19 vaccinated pregnant women. She notes that it can be harmful to the baby when a pregnant woman runs a high fever. “If that is a side effect, you’d want to pay attention to that and talk to your provider about taking something to reduce the fever,” she says.

There are clinical trials in the pipeline to investigate the effects of the vaccines in pregnant women. Faden wishes these trials had started as soon as the vaccines received FDA approval, but she points out that the process is still moving more rapidly than it has in the past.

“We used to feel like one or two lonely drums out there, beating our drums in this vast silence,” she says. “Now we’ve got like a whole percussion section calling for more data and the inclusion of pregnant women in the rollout of the vaccine. And that’s a really good thing.”

The risks of infection

On the flip side, we do know plenty about the risks getting COVID-19 poses to expectant parents. “There’s no question at all that pregnant women fare worse than not-pregnant people,” Swamy says.

Studies have shown that pregnant people with COVID-19 are at an increased risk for hospitalization, ICU admission, and mechanical ventilation. In January, a study published in the journal JAMA Internal Medicine found that COVID-19 was associated with higher odds of blood pressure problems and premature birth, though there weren’t greater chances of stillbirth. And a study in October found that one in four pregnant people may be COVID-19 “long-haulers,” whose symptoms can linger for weeks or even months.

But the risk of severe illness is lower for the expecting than for other high-risk groups, such as the elderly or those with heart disease. So it’s critical to look at individual factors that increase a person’s individual risks—including numbers of daily contacts, access to testing and high-quality PPE, and comorbidities such as asthma or obesity—and whether there’s anything that can be done to reduce them.

Timing has to be taken into consideration, too. Swamy says there’s no evidence that a vaccine can cause developmental problems or miscarriage in the first trimester. But women at lower risk of infection may choose not to get vaccinated during that period, which is vital for fetal organ development and is when miscarriages typically occur. (The influenza vaccine is safe at any point during pregnancy.)

For pregnant women who are at high risk of exposure and who don’t have the option of reducing that risk, it may make sense to consider getting the vaccine as soon as they’re eligible. But to find out for sure, Chambers says, “the urgency is to get the data on people who are getting vaccinated.”

What we’re still trying to find out

There’s reason to hope that scientists will soon have a better understanding of how the COVID-19 vaccines work during pregnancy. In the near term, scientists are looking forward to the data from pregnant health-care workers who began taking the vaccines in December. Faden says that data should be robust, since more than 15,000 pregnancies among the vaccinated were reported to the CDC as of January 20.

Beyond the mRNA vaccines, there are some new options on the horizon. Johnson & Johnson submitted its vaccine for FDA approval on February 4, while AstraZeneca and Novavax have recently released critical phase three trial data. All three vaccines rely on technologies that have been studied in pregnant women in the past, which Swamy says could provide further reassurance.

Recent studies have also suggested that there could be extra benefits to vaccination while pregnant. One study published in the journal JAMA Pediatrics showed that women who have been infected with COVID-19 efficiently transfer protective antibodies to their babies—particularly if infected earlier in the pregnancy. The study does not suggest this transfer will happen after vaccination, notes co-author Karen Puopolo, attending neonatologist at Pennsylvania Hospital. But Swamy says it’s good news that antibodies are regularly crossing the placenta in natural infection, and that she expects vaccination would have a similar response.

“It tells us that vaccinating women could have that kind of two-for-the-price of-one,” she says, “that by vaccinating women we’re also providing some benefit during early childhood.”

Pfizer and Moderna vaccines safe for pregnant people, major study confirms

The report strengthens the CDC’s recommendation that anyone pregnant be offered the vaccine and sets the stage for more “paradigm-changing” vaccine trials during pregnancy.

(Update 5/8/2021)

As each of the FDA-authorized COVID-19 vaccines became available, the Centers for Disease Control and Prevention consistently asserted that they should not be withheld from people who are pregnant and want the vaccine. But since all the clinical trials excluded people who were pregnant, no safety data was available for those who had to make that choice.

Now, since tens of thousands of people have chosen to get vaccinated while pregnant, the largest retrospective study yet provides strong evidence of the mRNA vaccines’ safety during pregnancy. The findings come soon after research confirmed the seriousness of COVID-19 during pregnancy, including an increased risk of preterm birth and stillbirth. Two other studies have also shown that vaccinated mothers pass more protective SARS-CoV-2 antibodies on to their newborns than mothers who had COVID-19 while pregnant.

The safety study, published April 21 in the New England Journal of Medicine, relied on multiple vaccine surveillance systems from December to February to assess the safety of the Pfizer/BioNTech and Moderna vaccines in more than 35,000 pregnant women. The study found no increased risks during pregnancy or birth complications or identifiable risks to the fetus among those who received the vaccine. When CDC Director Rochelle Walensky highlighted the findings at an April 23 briefing, she seemed to suggest the agency was updating their official recommendations for this population.

“As such, CDC recommends that pregnant people receive the COVID-19 vaccine,” Walensky said. “We know that this is a deeply personal decision, and I encourage people to talk to their doctors or primary care providers to determine what is best for them and for their baby.”

Protecting mothers is the priority with COVID-19 vaccination because of the risk the disease poses in pregnancy. An April 22 study in JAMA Pediatrics found a greater risk of preterm birth, preeclampsia (a dangerous high blood pressure condition in pregnancy), admission to the ICU, and death in pregnant women with COVID-19 compared to pregnant women without an infection. Both mothers and newborns were more likely to have severe complications of any kind in pregnancies with COVID-19. Even asymptomatic women had a higher risk of preeclampsia and maternal complications. Similarly, a recent meta-analysis of studies involving more than 430,000 pregnant people found that COVID-19 during pregnancy doubled the risk of stillbirth as well as raised the risk of preeclampsia and preterm birth.

Walensky’s comments initially caused confusion when it was widely reported after the briefing that the CDC was changing its guidance to recommend COVID-19 vaccination in pregnant people. CDC vaccine recommendations come from the Advisory Committee on Immunization Practices (ACIP), which had not announced any changes to guidance for mRNA vaccines during pregnancy, and guidelines on the CDC website have not changed.

The CDC did not respond to a request for comment by press time, but CBS News reported that the agency had partly clarified Walenksy’s statement, specifying that Walensky “was conveying that CDC recommends pregnant people be offered the vaccine.”

“The CDC is trying to balance allowing pregnant women, because they’re at risk, to have access to the vaccine,” Carol Baker, a professor of pediatrics at UTHealth in Houston, says. “The CDC is trying to give wiggle room for the whole conversation about risk-benefit.”

The new study offers the best news yet for those considering the vaccine while pregnant, says Linda Eckert, a professor of obstetrics and gynecology at the University of Washington School of Medicine in Seattle.

“I’m very happy to see this data coming in and that the safety data so far are reassuring,” Eckert says. “We haven’t seen any increased risk of adverse pregnancy outcomes in women who are immunized with the COVID vaccine compared to those who are not.”

Baby receives protective antibodies

A subset of nearly 4,000 participants in the study enrolled in the v-safe pregnancy registry—designed to track adverse events in vaccine recipients after their shots—including 29 percent in their first trimester, 44 percent in their second trimester, and 25 percent in their third trimester. Among the 827 in this group who completed their pregnancy, 86 percent had a live birth. Nearly all of the 14 percent who had a pregnancy loss (92 percent) were in their first trimester. That is consistent with numbers during non-pandemic times, according to the study, when 10 to 26 percent of all first-trimester pregnancies result in miscarriage.

Rates of preterm birth (9 percent), infants underweight for their week of delivery (3 percent), and birth defects (2 percent) in the vaccinated cohort were in the same range as those seen in pre-pandemic pregnancy research.

The most common side effects women experienced were pain at the injection site, fatigue, headache, and muscle aches. Less than one percent of participants had a fever of at least 100°F after the first dose and less than 8 percent had one after the second dose. Overall, pregnant women experienced more arm pain but less systemic reactions than similarly aged women who were not pregnant.

A week after that study’s publication, a pair of studies in Obstetrics & Gynecology found that infants receive substantially more antibodies against SARS-CoV-2 from mothers who received an mRNA vaccine during pregnancy than from mothers who had a COVID-19 infection during pregnancy. This research reaffirms findings in March that found a stronger immune response from mRNA vaccines than from COVID-19 in pregnant women and detected maternal antibodies in breastmilk and in newborns’ umbilical cord blood, which indicates the infants’ antibody levels.

“That there’s good transplacental antibody transfer is not surprising,” Ruth Karron, a professor of international health and director of the Center for Immunization Research at Johns Hopkins Bloomberg School of Public Health, says. “It’s consistent with what we see with other pathogens, and it’s a potential additional benefit of the immunization of pregnant women.”

Starting around the second trimester and then ramping up in the third is “a mechanism for shoveling antibodies from the maternal side to the fetal side of the placenta,” Karron says. That’s true for most of a subset of the mother’s antibodies known as IgG, but antibodies against proteins—such as the coronavirus spike protein—transfer especially efficiently, Baker adds.

There is strong evidence that SARS-CoV-2 maternal antibodies, induced by vaccines, transfer to the fetus. This antibody transfer is also true for the pertussis (Tdap) and annual influenza vaccines, both of which are recommended during pregnancy. The goal of pertussis vaccination, recommended between weeks 27 and 36 of pregnancy, is to protect infants in their first few months against whooping cough, whereas the flu shot is intended to protect the mother as well as the baby, Karron says.

Vaccine trials in pregnant participants “paradigm-changing” 

COVID-19’s threat during pregnancy is what led vaccine manufacturers to begin trials in pregnant women, says Sandra Hurtado, an obstetrician/gynecologist with McGovern Medical School at UTHealth in Houston, and the principal investigator for the Pfizer/BioNTech clinical trial site there.

Pfizer is recruiting people between 24 and 34 weeks of pregnancy for the international phase two and three placebo-controlled trial that will enroll 351 participants for phase two and 3,660 participants for phase three. The trial focuses on safety and testing antibody levels in participants, in their newborns at birth, and in the infants at six months old. Johnson & Johnson has plans for a trial in pregnant women, but Moderna has not announced plans.

The Pfizer/BioNTech trial includes 83 locations in the U.S., but the trial only started in February. Since the vaccine has been available to pregnant people for several weeks or longer, recruitment is a challenge.

“The women who want the vaccine are going to go ahead and get vaccinated, and the women who don’t want the vaccine are waiting to be vaccinated later or won’t be vaccinated at all, so it’s difficult to enroll patients,” Hurtado says.

Since the trial is focused more on safety than on effectiveness, and since restricting people from getting a vaccine in a pandemic would be unethical, participants will be unblinded one month after delivery and offered the vaccine if they received the placebo, she says.

Experts, including Karron, have called for trials in pregnant women for months, but testing vaccines during pregnancy has always been contentious, says Baker. Until the 2009-2010 H1N1 influenza pandemic, when the danger of H1N1 to pregnant women and their need for immunization became clear, such trials were almost unheard of.

“There was a real interest at that time to make sure in any future pandemic we would enroll pregnant women in those studies,” says Kevin Ault, professor of obstetrics and gynecology at the University of Kansas Medical Center. “The problem we had this time is it wasn’t clear for the first six to eight months while those studies were being designed that pregnant women were at increased risk [from COVID-19].”

That data emerged in fall, when the trials were well underway. “Had we known that right off the bat, we might have designed things differently,” Ault says.

The fact that trials are occurring even now is “paradigm-changing,” Baker says. “I’m very personally and professionally pleased that the concept of immunizing pregnant women to protect themselves and their young infants from vaccine preventable disease has leapt forward by great bounds,” she says. “I think this will change the way we go forward.”

Questions remain regarding J&J vaccine

Despite the safety data now available for mRNA vaccines, the equivalent data isn’t yet available for the Johnson & Johnson vaccine. Experts are split on what that means since the discovery that the vaccine can, in extremely rare cases, cause blood clots. Unlike the mRNA vaccines, which consist of mRNA encapsulated within a lipid droplet, the J&J vaccine uses a deactivated adenovirus as a vector to carry DNA into the body. Scientists suspect the adenovirus vector may be what triggers the rare blood clot reaction in some people.

Eckert noted that the clots associated with the J&J vaccine differ from the type of clots that people have a higher risk of developing during pregnancy. That said, the risk is only about 7 clots per million doses in women aged 18-49, per a CDC clinical update. Eckert doesn’t explicitly advise against the J&J vaccine and says some of her patients prefer the single shot.

Ault wants to see more data before recommending one vaccine over another. Karron, however, has argued that women under 50 should preferentially receive mRNA vaccines because we lack data on clot risk from the J&J vaccine during pregnancy. Baker agrees, noting that some healthy women without risk factors nevertheless develop clots during pregnancy.

“It’s rare, but I would avoid vaccines that have even a rare complication of thrombi [blood clots] of any kind just because pregnancy is a thrombus-risk time,” Baker says. She also thinks waiting to get vaccinated until late in the second trimester or early in the third is ideal because it’s at the beginning of viability, when all fetal organs are fully formed. It is also when the greatest antibody transfer from mother to the fetus occurs. Further, the third trimester is when the most severe COVID-19 complications are likely in pregnant people, Karron adds.

Ault and Eckert do not make any recommendations about getting the vaccine during a particular trimester. When they bring up the vaccine to patients, they ask what the patient thinks about the vaccines and whether they can answer any questions or offer information to the patient. Both have seen the full spectrum of hesitancy to enthusiasm about the vaccines and have lately seen vaccine confidence rising. Eckert says she shares with patients her opinion that the benefits outweigh the risks and her concerns about the dangers of COVID-19 during pregnancy but doesn’t pressure patients.

“I stop short of saying you should absolutely get it,” Eckert says, “but I come very close.”

The vaccine alternatives for people with compromised immune systems

Drug makers are increasingly turning to monoclonal antibodies to protect the millions of people who may not be able to use vaccines. But questions swirl about their cost and long-term viability.

As the COVID-19 vaccine rollout gathers pace, a population is at risk of being left behind: the millions of people around the globe who lack fully functional immune systems.

While the exact number of the immunocompromised worldwide is unknown, estimates suggest that about 10 million live in the U.S. alone, or around 3 percent of the national population. The number encompasses a diverse range of vulnerabilities, including rare genetic immune deficiencies, chronic illnesses that impair the immune system such as rheumatoid arthritis, and cancer and organ-transplant patients who must take immune-suppressing medications.

For them, vaccines may not be as effective, because they are less capable of making their own antibodies to neutralize the SARS-CoV-2 virus. Instead, pharmaceutical companies around the world are racing to develop alternative treatments that bypass the immune system altogether.

The most common option is called monoclonal antibody treatments. These artificially generated antibodies mimic the body’s natural immune response by binding to key sites on the virus’ spike protein, preventing it entering cells and reproducing. Companies including AstraZeneca, Regeneron, and Eli Lilly are currently testing whether monoclonal antibodies can protect immunocompromised people from SARS-CoV-2.

“You often find that patients who have had bone marrow transplants end up getting terrible flu and other infections, which they can’t clear without additional help,” says Nicky Longley, an infectious diseases consultant at University College London Hospitals. “It was these heavily immune-suppressed populations who did very badly during the first wave of COVID-19.”

In addition, preventing immunocompromised people from getting infected will be a key part of keeping the disease in check in the long run, says Andrew Ustianowski, an infectious disease specialist at the U.K.’s National Institute for Health Research.

“If we want to control this virus and get back into normal life, then being able to protect everybody, so we don’t have ongoing transmission in subgroups of the population, is important,” he says.

But while many scientists are excited about the potential of monoclonal antibodies to address gaps in the world’s vaccination programs, questions remain. The coming months will tell us whether these treatments are sufficiently cost-effective to be used on a large scale, if they can really provide adequate protection for months at a time, and whether using monoclonal antibodies may inadvertently do more harm than good.

A potential ‘game changer’

In the past, the only alternative means of protecting immunocompromised people during viral outbreaks was a product called intravenous immunoglobulin, or IVIG. Taken from the blood plasma of healthy donors, infusions of IVIG are one way of supplying patients with natural antibodies against a broad range of infections most people are commonly exposed to.

But supplies are limited, and IVIG is expensive, with a single patient’s cost sometimes reaching up to $30,000 a year. It also provides protection for only three weeks at a time, as the antibody concentrations in the product slowly wane, and it isn’t guaranteed to work against any specific virus.

“If you could get them a more targeted form of passive immunization which is made synthetically, it could be a real game changer,” says Longley.

However, creating monoclonal antibodies is also a painstaking process. It involves first extracting a broad range of antibodies from the blood of recovering patients, testing them in animals to identify which are best at neutralizing the virus, cloning the chosen ones in the lab, and then growing them in sufficient quantities in gigantic steel bioreactors.

Because of the time it takes to make a finished product, monoclonal antibodies were long considered impractical against viruses. Over the past decade, they have been most commonly used as treatments for cancer and autoimmune diseases.

“Viruses mutate rapidly, so scientists might well find the perfect site, begin production of the perfect monoclonal antibody, and then all of a sudden the virus mutates so the antibody doesn’t bind as well, or worse, doesn’t bind at all,” says Rodney Rohde, professor of clinical laboratory science at Texas State University.

But various research programs have driven a number of technological advances in recent years. Antibodies can now be isolated from convalescent patients in less than a month, while virologists have got progressively better both at identifying sites in the viral genome that are less likely to mutate. Five years ago, the quickest time frame for creating monoclonal antibodies was 18 months. Today, it’s about 10 months.

Even more crucial, scientists have tweaked the underlying structure of monoclonal antibodies, making it harder for the body to remove them from the bloodstream—meaning they can potentially last for months at a time rather than weeks.

These developments had initiated renewed interest in monoclonal antibodies as virus fighters even before the COVID-19 pandemic. A study published in December 2019 found that such treatments reduced mortality during an Ebola outbreak in the Democratic Republic of the Congo by 15 percent. And that autumn, the National Institute of Allergy and Infectious Diseases (NIAD) funded a research program to assess the viability of identifying monoclonal antibodies for use against seasonal influenza.

Now, Ustianowski is leading a global clinical trial called PROVENT, in conjunction with AstraZeneca, that’s attempting to find monoclonal antibodies that will work against SARS-CoV-2. In the PROVENT trial, 5,000 people around the world with various immune deficiencies will receive a dose of either a monoclonal antibody-based cocktail or a placebo. They’ll be followed over the course of a year to see whether the treatment prevents them getting COVID-19, and how long protection lasts.

If PROVENT is successful, Longley suggests that the treatment could also be used to protect people who produced too few natural antibodies in response to the vaccine, such as elderly individuals whose immune systems are not as active. This would mean that even though they have had the vaccine, they are not protected. “Vaccines take a bit of time to build immunity in the body, but injecting monoclonal antibodies should work immediately, so it could work as a preventative measure,” she says.

Both Eli Lilly and Regeneron are already looking at whether these antibodies can offer protection to nursing home residents in areas where the vaccine rollout has been delayed. Last week, Eli Lilly released data from a phase three trial which showed that its monoclonal antibody treatment bamlanivimab reduced the risk of contracting COVID-19 by up to 80 percent in care facilities.

In the longer term, with COVID-19 widely expected to develop into an endemic disease, Ustianowski predicts that monoclonal antibodies could be used as periodic boosters every six months to a year to protect vulnerable immunocompromised people even after herd immunity has been achieved in the general population.

“Coronavirus is not going to disappear from the Earth over the next few years,” he says. “For those at ongoing risk, I could imagine them receiving these periodic injections.”

Fears of an access gap

One of the major hurdles for monoclonal antibodies has always been the staggering costs. While seven of the top 10 best-selling drugs of 2019 were monoclonal antibodies for cancer and autoimmune diseases, one study found the average annual price per patient worked out to be $96,731. Access has therefore been restricted to only the wealthiest nations. Currently, 80 percent of global sales of licensed therapeutic antibodies are in the U.S., Europe, and Canada.

Pharmaceutical companies making monoclonal antibodies for COVID-19 insist that the price tag per dose will not be in the tens of thousands.

“We’re not ever going to be talking about a price for these drugs that’s of the order of $100,000,” says Alexandra Bowie, a spokesperson for Regeneron. “If you look at what we’ve done so far, the price per dose for the contracts we’ve signed with the U.S. government is more on the order of $2,000.”

However, $2,000 is still significantly more expensive than vaccinations, and the price may prove unaffordable in many parts of the world. By comparison, the Pfizer-BioNTech jab costs $20 per dose, and the AstraZeneca vaccine comes in at just $4 per dose. On balance, though, Ustianowski argues that it’s better to have the drugs available for the smaller portion of the population that really needs them.

“This isn’t for everybody; it’s just for those that can’t have the cheaper and more cost-effective vaccines,” Ustianowski says. “If you’re talking about a subset of individuals, then it’s easier to encompass that cost.”

Steps are already being taken to address the potential access gap. Bowie says that the U.S. government has so far committed to making 1.5 million doses ordered from Regeneron free for patients, regardless of whether they have health insurance. Currently this batch is being used as treatments for non-hospitalized patients with mild to moderate cases of COVID-19, though future supplies could be used as passive immunizations pending regulatory approval. In addition, she says a donation strategy will be put in place specifically for lower- and middle-income countries, in conjunction with their manufacturing partner, Roche.

Jens Lundgren, an infectious disease physician at the University of Copenhagen, also expects pharmaceutical companies will strike deals with generic drug manufacturers in lower-income nations.

“The actual production price once you have the antibody clones developed is very minimal,” he says. “This is why you can already see generic manufacturers in Asia producing monoclonal antibodies for some autoimmune diseases and selling them at a very low price per dose.”

Safety first

But cost is only one of the concerns surrounding monoclonal antibodies. There are safety issues to consider, which will be monitored closely in both the PROVENT trial and other clinical trials.

One of these is a troubling phenomenon called antibody-dependent enhancement, which was observed by scientists trying to create vaccines against dengue fever. Receptors on the tail region of antibodies normally bind to immune cells, allowing antibodies to activate the immune system. In some cases, though, it seems these receptors can accidentally attach to viruses too, allowing the pathogens to access cells rather than stopping them. Monoclonal antibody manufacturers are now taking steps to minimize that likelihood, such as engineering receptors with mutations that limit the risk of virus binding.

Another major issue is whether monoclonal antibodies could quickly become obsolete as new variants of SARS-CoV-2 emerge, something which is already proving to be a challenge. Recent studies conducted in the U.S., South Africa, and China suggest that Eli Lilly and GSK’s products, which each consist of a single monoclonal antibody, may not work against one or more of the three major variants of SARS-CoV-2. These papers were released on the bioRxiv preprint server and are not yet peer reviewed.

Regeneron’s product consists of a cocktail of two monoclonal antibodies, and the data suggest it is still effective against the variants. Eli Lilly and GSK are testing whether combining their products into an antibody cocktail can improve efficacy. There is no data yet for how AstraZeneca’s monoclonal antibody product fares against the variants.

Another theory suggests that using these products as emergency treatments for hospitalized patients could encourage viral evolution. A recent lab study found that the virus is indeed capable of deliberately mutating to evade multiple antibodies found in convalescent plasma. If monoclonal antibodies derived from this plasma do not immediately inactivate the virus, they may encourage it to mutate further, creating new variants.

At the same time, many scientists involved in monoclonal antibody research believe that greater use of them as passive immunizations in vulnerable populations could actually help stop new variants from appearing.

“For most of 2020, the majority of the population was immunologically naïve to this virus, and thus the virus was freely circulating among vulnerable individuals, including the immunocompromised individuals,” says Ali Ellebedy, assistant professor of pathology and immunology at Washington University School of Medicine. In the immunocompromised, the virus can keep replicating—and thus mutating—in the same person for weeks, providing what Ellebedy calls the “perfect platform” for new variants to emerge. In theory, protecting more of these vulnerable people can thus limit the virus’s chances of spawning new variants.

For the scientists leading the PROVENT trial, much depends on the coming months and whether monoclonal antibodies can be shown to provide long-lasting protection in vulnerable populations. If so, they feel this will open doors for monoclonal antibodies protecting more immunocompromised patients as part of standard medical care.

“If effective, I could see these immunizations being used in some cancer patients, for example those who are being treated for acute leukeumias,” says Longley. “They can’t have vaccines, and you’re worried about them being exposed during a flu or a measles outbreak. This could keep them safe until they have their curative treatment.”

The complex situation for immunocompromised people and COVID-19 vaccines

(Updated 6/19/2021)

Studies suggest the available shots don’t provide enough protection, leaving more than nine million Americans with compromised immune systems stuck in a waiting game

When Margaret Collins, a 43-year-old geologist from Fort Worth, Texas, got her first dose of the Moderna vaccine January 6, she came home and cried.

“I was finally getting the shot,” she says. “I saw it as a step back to the life that I loved.”

A self-described extrovert, Collins became a hermit during the pandemic. She and her husband rarely stepped outside, and never without a mask. Her caution is warranted because she suffers from a generalized autoimmune disorder that includes hepatitis, psoriatic arthritis, vitiligo, and type 1 diabetes. Collins is also particularly vulnerable to COVID-19 because she received a donated pancreas and kidney in 2014 and takes three medications to suppress her immune system so her body doesn’t reject those organs. Yet, vaccines work by harnessing the capability of a fully competent immune system.

Since the FDA authorized the first COVID-19 vaccine, people with compromised immune systems have lived in limbo, waiting to find out whether, or how much, vaccination might protect them. The vaccine clinical trials excluded nearly all immune-compromised people because including them might interfere with determining vaccine effectiveness for the general population. But that’s left this group with little data on what vaccination means for them. Now studies are trickling in.

“We’re starting to learn some of the things we don’t know, whereas before, it was a bunch of we don’t know what we don’t know,” says Peter Martin, a hematologist and oncologist at Weill Cornell Medicine in New York City.

It’s difficult to gauge the number of immune-compromised people in the U.S. One study estimates that 2.8 percent of people with private insurance take immune-suppressing drugs—about nine million Americans. But that doesn’t include Medicare or Medicaid patients, who are more likely to have some conditions requiring immunosuppression, says study author Beth Wallace, a rheumatologist at University of Michigan Medicine. It also doesn’t include people with immune-compromising conditions who aren’t taking immune-suppressing medications.

From the very beginning of the pandemic Collins worried how her body would respond to the vaccine. But when she later read a study of organ transplant recipients that found low antibody levels after the first mRNA vaccine dose, she panicked.

Even though she had been vaccinated and wore a mask, she thought “How safe was I? It really scared me.”

follow-up study that found about half of transplant recipients responded to the vaccine offered her little comfort. “That’s essentially the flip of a coin,” Collins says. But a small study published Monday offers a flicker of hope.

After two doses of mRNA vaccine, 30 transplant recipients with no or low antibodies got a third shot, though not necessarily of the same vaccine they received first. The six people with low antibody levels subsequently developed higher levels, and a quarter of the others, who had never responded to the COVID-19 vaccine, developed antibody levels thought to be high enough to prevent COVID-19 after the third dose.

But this study has substantial limitations: It’s very small and involves a grab bag of different vaccine combinations. Further, the Food and Drug Administration has not authorized a third dose, and the Centers for Disease Control and Prevention currently advises against it. The authors concluded that their findings suggest the need for more studies to test third doses in people without fully functioning immune systems.

A diverse population

Immune-compromised people fall into two broad categories: Either they have an underlying condition that weakens their immune system, such as people with leukemia, uncontrolled HIV, or a rare genetic disease, or they have an underlying condition requiring immune-suppressing therapy, such as organ transplant recipients and people with rheumatic diseases (inflammatory, autoimmune conditions) or some cancers. A few conditions, such as chronic lymphocytic leukemia and lupus, fall into both categories.

Factors that might affect someone’s response to a vaccine include the medication they’re taking and what it does, how long they’ve been taking it, their specific disease, and their history of infection. For organ transplant recipients, the time since their transplant may also matter.

“That’s why it’s really important for people who have these immune-suppressed conditions to talk to an expert about their specific situation, because there is such a great amount of variability,” says Aaron Richterman, an infectious disease fellow at the University of Pennsylvania Perelman School of Medicine, regarding how immune-compromised people can assess their infection risk after vaccination.

Evidence so far is mixed

The wide range of conditions and drugs that weaken the immune system explain why the response to COVID-19 vaccines is so mixed. The evidence so far shows that transplant recipients, certain leukemia patients, and people taking a handful of specific medications have the poorest vaccine response. The drugs that appear linked with the poorest response include mycophenolate (prevents organ rejection), rituximab (treats some blood cancers and autoimmune diseases like rheumatoid arthritis), belatacept (prevents organ rejection), and methotrexate (treats a wide range of cancers and autoimmune diseases).

For example, the organ transplant study Collins read found only 54 percent of 658 organ transplantrecipients had any antibodies after two doses of the mRNA vaccine, particularly if they were taking a drug like mycophenolate. A similar study of 609 kidney transplant recipients found half had detectable antibodies after mRNA vaccination, but only 5 percent of those taking belatacept did. Transplant recipients produced even fewer antibodies in response to the one-dose Johnson & Johnson vaccine.

Studies in people with autoimmune disease have similarly shown that vaccine response typically depends on the specific drug they’re taking.

In a study of 404 people with rheumatic disease who had both doses of an mRNA vaccine, almost all had detectable antibodies, but those taking rituximab or mycophenolate had very low levels. Meanwhile, everyone taking anti-inflammation drugs called tumor necrosis factor (TNF) inhibitors to treat Crohn’s disease or rheumatoid or psoriatic arthritis, had strong antibody responses.

Another study (preprint) of 133 people had similar findings: Antibody levels were 1/50 as high in people taking rituximab, a drug that intentionally depletes antibody-producing B cells, as in people with competent immune systems. Those taking certain chemotherapy drugs, rheumatoid arthritis drugs, or prednisone—a steroid that treats inflammation—also had lower antibody levels.

People with certain types of leukemia or lymphomas, particularly non-Hodgkin’s lymphoma and chronic lymphocytic leukemia, also don’t produce many antibodies after vaccination, though people with most other cancers fare better. That’s particularly concerning since some people with CLL don’t know they have it, says study author Mounzer Agha, director of the Mario Lemieux Center for Blood Cancers at University of Pittsburgh Medical Center.

Those are just a sampling of the studies examining different immunecompromising conditions and medications, but all are small, providing only some insight into these specific conditions or therapies.

“What matters is how much immunosuppression you’re getting, what agents you’re getting, and possibly how long you’ve been getting them,” says Dorry Segev, a transplant surgeon and researcher at Johns Hopkins Medicine who wrote the organ transplant studies and several others above.

More than just antibodies

These studies also focus only on antibody response, which is just one component of the immune response.

“We think antibody levels may correlate to clinical protection to a degree,” Richterman says. But even in healthy people, he says, we don’t know the minimum antibody levels necessary to assure protection. Since the significance of antibody levels is ambiguous, the FDA and CDC recommend against antibody testing because it is unclear how to interpret the findings.

“Immunologic responses and effectiveness of a vaccine are two different things,” says Emily Blumberg, director of Transplant Infectious Diseases at Penn Medicine in Philadelphia. “We think vaccinating [transplant] patients may have a benefit above and beyond what you can measure with antibodies.”

That’s partly because vaccines induce immunity in multiple ways. One way is stimulating B cells to make antibodies, which explains why medications that reduce B cells—such as rituximab, methotrexate, mycophenolate, and steroids—result in such poor responses. But vaccines can also stimulate killer T cells, which attack infected cells, and helper T cells, which aid B cells and killer T cells.

“Our understanding of what’s happening on the T cell side is pretty close to zero,” Segev says. Studying T cell responses is difficult and costly, he adds, though his group and others are working on it.

Vaccines can also trigger the production of memory B cells, which remember how to make antibodies. “If you get the virus and the memory cells are there, then you can have a better and faster antibody response the next time around,” explains Ignacio Sanz, chief of rheumatology at Emory University School of Medicine. He believes that presence of memory B cells might partly explain why a third vaccine dose led to antibody production in transplant recipients without previous responses.

The only way to find out how effective the vaccines actually are in immune-compromised people is to wait fordata comparing infections between vaccinated and unvaccinated people in different immune-compromised groups, and that takes time.

What comes next

Where does all this leave the millions of people who don’t know if they are protected by the vaccine, especially with the CDC’s advice that vaccinated people can stop masking?

For now, “get vaccinated, act unvaccinated,” Segev says. But that’s a difficult message to communicate.

“One of the unintended consequences of [that message] is fueling vaccine hesitancy in patients who say, ‘Why should I bother if I’m not going to have a response?’” Blumberg says.

February study of more than 1,200 people with autoimmune disease found that more than half wanted to get vaccinated, and a third were uncertain, despite studies showing the vaccines are safe for those with inflammatory diseases.

Alfred Kim, a rheumatologist at the Washington University School of Medicine who conducted one of the studies on people with rheumatic disease, agrees it can be confusing to advise patients to get vaccinated without being able assure it protects them, but “even partial protection is better than no protection,” he says.

That introduces another problem: How safely can immune-compromised people go out in public even if vaccinated?

“The CDC guidelines assume everybody is socially responsible, which unfortunately is not the case,” Agha says.

“Masks work, but masks work best if everybody is wearing them,” Segev says. “If you have a superspreader walking around Kroger spewing their Delta variant all over the store, and they’re standing next to an immunosuppressed transplant patient who tried their best to get vaccinated and is still wearing a mask, that [immunosuppressed] person is still at risk.”

While immune-compromised patients have always been more susceptible to infections, even before the pandemic, the stakes are higher now.

“With influenza, it was not such a great concern because patients do survive influenza even when they get quite ill,” Mounzer says. “With COVID, it’s a different story. There’s a real risk of dying from the disease.”

In a post-masking world, that makes even brief trips to the grocery store more complicated—and perilous—for immune-compromised people.

“As a society I think we have an obligation to come up with strategies to prevent those people from getting acutely sick so they can re-enter society like the rest of us are all ready to do,” Martin, the hematologist, says. “They’re just as ready as anybody else, and it’s terrifying to be in their position.”

Blumberg tells her patients to encourage friends, family members, and coworkers to get vaccinated. “The better job we do with vaccinating everybody, the less COVID there will be to make them sick,” she says.

That’s exactly what Collins, the vaccinated transplant recipient from Texas, is doing. But she has friends and family members who refuse to get vaccinated, and that frightens her, not only for herself but also for other immune-compromised family members and friends.

“If we reach herd immunity, then I have less to worry about,” Collins says. But she doesn’t think the country will reach that milestone, “which is scary for people like me.”

If social responsibility does not motivate people to get vaccinated, there’s also the specter of new variants. Evidence suggests that people whose immune systems don’t respond properly to infection could provide an ideal environment for mutations, says John Moore, a microbiologist and immunologist at Weill Cornell Medicine in New York City. “They have a lot of ongoing viral replication in their bodies for prolonged periods of time,” Moore says. “Virus replication in an antibody-low individual can drive the emergence of variants that are problematic on a societal basis, so this is not a trivial issue.”

In other words, protecting the most vulnerable members of society is ultimately the best way to protect all of society.

“These are the patients that are going to be a source of continued infection in the population,” Blumberg says. “If we don’t protect these immuno-suppressed hosts, we will have a harder time getting rid of the virus.”

Why your arm might be sore after getting a vaccine

(Updated 3/19/2021)

For most COVID-19 vaccine recipients, the poke of the needle is no big deal. In the hours afterwards, however, many go on to develop sore arms, according to anecdotal reports and published data.

That common side effect is not unique to COVID-19 vaccines. But as the United States undergoes its first mass vaccination campaign in recent memory, the widespread prevalence of arm pain is sparking questions about why certain shots hurt so much, why some people feel more pain than others, and why some don’t feel any pain at all.

The good news, experts say, is that arm pain and even rashes are normal responses to the injection of foreign substances into our bodies. “Getting that reaction at the site is exactly what we would expect a vaccine to do that is trying to mimic a pathogen without causing the disease,” says Deborah Fuller, a vaccinologist at the University of Washington School of Medicine, in Seattle.

Given the many intricacies of the immune system and individual quirks, not feeling pain is normal, too, says William Moss, an epidemiologist and executive director of the International Vaccine Access Center at the Johns Hopkins School of Public Health in Baltimore. “People can develop protective immune responses and not have any of that kind of local reaction,” he says.

Danger signals

A variety of vaccines are notorious for the soreness they cause around the injection site, and the explanation for why begins with so-called antigen-presenting cells. These cells are constantly on the prowl in our muscles, skin, and other tissues. When they detect a foreign invader, they set off a chain reaction that eventually produces antibodies and long-lasting protection against specific pathogens. That process, known as the adaptive immune response, can take a week or two to ramp up.

Meanwhile, within minutes or even seconds of getting vaccinated or detecting a virus, antigen-presenting cells also send out “danger” signals that, Moss says, essentially say, “‘Hey, there’s something here that doesn’t belong. You guys should come here. We should get rid of it.’”

This rapid reaction, known as the innate immune response, involves a slew of immune cells that arrive on the scene and produce proteins known as cytokines, chemokines, and prostaglandins, which recruit yet more immune cells and have all sorts of physical effects, Fuller says. Cytokines dilate blood vessels to increase blood flow, causing swelling and redness. They can also irritate nerves, causing pain. Cytokines and chemokines induce inflammation, which is also painful. Prostaglandins interact directly with local pain receptors.

The innate immune response doesn’t stop at the arm. For some people, the same inflammatory process also can cause fevers, body aches, joint pain, rashes or headaches.

The reason some vaccines cause more symptoms than others—a tendency called reactogenicity—is because of the strategies and ingredients they employ. The vaccine for measles, mumps, and rubella (MMR), for example, is made from live, weakened forms of the viruses that intentionally cause a mild form of infection and stimulate the body’s innate immune response, leading to a variety of symptoms, including sore arms. Other vaccines, including some flu shots, introduce inactivated viruses. The hepatitis B vaccine presents parts of the virus along with chemicals called adjuvants that are designed to get antigen-presenting cells riled up and boost the adaptive immune response.

Those substances, Fuller says, “are the first trigger your body gets to say, ‘Something is going on here, and I need to respond to it.’”

Sore-arm profiles

All three FDA-approved COVID-19 vaccines are delivered via a needle into the arm, and all cause the same kind of poking pain that comes with a quick stab. After that, their post-vaccination arm-soreness profiles vary, according to company data compiled by the Centers for Disease Control and Prevention.

After the first dose of the two-shot Moderna regimen, 87 percent of people under 65 years old and 74 percent of those 65 and up in clinical trials reported localized pain, echoing research that shows a decline in immune reactivity with age. After the second shot, those numbers rose to 90 percent of the younger age group and 83 percent of older people.

The first Pfizer shot, likewise, caused a lot of sore arms in trials: 83 percent of people up to age 55, and 71 percent in older people. Shot-two soreness occurred in 78 percent of the younger group and 66 percent of the older one.

The one-dose Johnson & Johnson vaccine caused less arm pain—59 percent of people under 60 and 33 percent of older people.

The elevated rates of arm pain with the Pfizer and Moderna vaccines might have something to do with technology they use, Fuller says. Unlike J&J, which uses a modified virus to deliver a gene that directs our cells to make the SARS-CoV-2’s spike protein, Pfizer in Madera deliver instructions for making the protein via mRNA. Researchers have long known that RNA, which some viruses use to carry their genetic material, is a potent trigger of the innate immune system.

In fact, she says, when scientists started considering mRNA as a vaccine strategy some 30 years ago, they rejected the idea, in part because of concerns that it would overstimulate inflammatory pathways. They were also too unstable to work. More recent breakthroughs in the ability to modify mRNA and encapsulate it in lipid nanoparticle coatings made the new generation of vaccines possible, but common adverse reactions remain relatively high. The nanoparticle coating itself acts as an adjuvant that likely contributes to local reactions, Fuller adds.

A more surprising reaction

Soon after the Moderna vaccine was approved in December, allergist and researcher Kimberly Blumenthal began receiving photographs of arms from colleagues at Massachusetts General Hospital in Boston. The photos showed large red splotches around patients’ injection sites. Some people had a second rash below the first. Some had red marks shaped like ringed targets. Some rashes appeared on elbows and hands.

After accumulating a dozen images, Blumenthal wrote a letter for the New England Journal of Medicine with the goal of alerting physicians—and reassuring them—about the potential for delayed reactions to the vaccine. Some doctors were prescribing antibiotics for suspected infections, but the pattern she saw suggested that antibiotics were not necessary.

Unlike the rare and dangerous anaphylactic reaction that can happen immediately after injection, delayed rashes don’t usually require treatment, Blumenthal says. In a biopsy of one patient, she and colleagues found a variety of T cells, suggesting a type of hypersensitivity. Delayed rashes are known to show up occasionally after other vaccines too, she adds, and they can be a sign of hypersensitivity or a normal part of the immune response. Researchers don’t yet know which is happening with the Moderna vaccine. In this case, they may appear especially common because so many people are getting vaccinated at once.

Still, late-onset rashes might be more common than official data suggest. In clinical trials, Moderna reported them in 0.8 percent of vaccine recipients four or more days after the first shot, and in 0.2 percent of people after the second dose. But delayed rashes tend to appear an average of seven or eight days after injection, and initial trials weren’t designed to pick up on all symptoms that showed up that late, Blumenthal says, likely because they weren’t expecting them.

She has created a registry for physicians to report delayed rashes and is working on one for patients, in order to understand the range of what they can look like and detect any patterns about which rashes might be more worrisome. “Since we published this,” she says, “my in-box has been flooded with photos.”

Who feels the pain?

Among the people I know who have been vaccinated so far, some have felt little to no soreness. Others couldn’t sleep for days because of the pain. One friend who got the Pfizer shot said it felt like he had been punched by a professional boxer.

For symptoms like arm pain, individual variation is the norm, and studies suggest multiple explanations. Age can diminish immune reactions, for example. So can higher BMIs, found a recent preprint study.

Genetics likely plays a role in varied and complex ways, experts say. And gender matters, too. In addition to a vast literature on sex differences and immunity, women appear to experience more side effects then men in response to a COVID-19 vaccine, according to emerging evidence, even though men seem to suffer a larger impact from the virus itself.

Pain perception is another X-factor. Everyone processes pain signals differently. And fear and anxiety can exacerbate the feelings of pain, says Anna Taddio, a pharmacy professor who studies pain related to medical procedures in children at the University of Toronto.

Studies show that fear of needles is an important barrier to vaccination for a significant number of people. A quarter of adults reported being afraid of needles in a 2012 study by Taddio and colleagues. According to one new analysis of 119 published studies, 16 percent of adults and 27 percent of hospital employees avoided flu shots because of needle fears.

Amidst efforts to get people vaccinated as quickly as possible, public health officials often overlook opportunities to make the experience more positive, says Taddio, who has developed an approach for reducing fear and promoting coping skills to improve the vaccination experience.

And there are plenty of simple ways to make people feel less anxious about needles. Helpful strategies, according to Taddio’s approach, can include reminding people to wear a short-sleeve shirt to the clinic to make it easy to access their arms; allowing them to bring someone for support; encouraging the use of distractions; deep breathing and topical anesthetics; and inviting people to ask questions so that they feel informed and prepared.

She also recommends that providers and public health officials talk about vaccines in neutral terms—emphasizing the ability to get protection from the coronavirus instead of scaring people with phrases like “shots in arms.”

“You can talk all you want about the COVID vaccines and how safe they are, but we’re not addressing the underlying issue for a whole chunk of people,” she says. “Where do you hear about how we’re going to make this comfortable for you?”

What we know so far about the effort to vaccinate children

(updated 4/3/2021)

To achieve herd immunity, experts say kids need to get vaccinated, reducing the virus’s ability to spread.

Millions of parents breathed a collective sigh of relief this week as the preliminary results of the Pfizer/BioNTech COVID-19 vaccine trial in 12 to 15 year-olds revealed what so many had been hoping for: The vaccine works in teens too.

“Jubilation—that was my response,” says Nia Heard-Garris, an attending pediatrician at Lurie Children’s in Chicago and assistant professor of pediatrics at Northwestern University Feinberg School of Medicine—and a parent herself. She wasn’t the only one feeling that way.

With nearly a third of the country having already received at least one dose of a COVID-19 vaccine and more than 2 million vaccinations occurring every day, the cloud of anxiety that has plagued the nation for the past year is finally beginning to lift. The end of the pandemic is in sight. Attaining herd immunity—the point at which transmission stops because the virus doesn’t have enough susceptible hosts to infect—now feels like a real possibility. But there’s a catch: The children must be vaccinated.

“We’ll never get to that population level of herd immunity until we vaccinate kids,” says Jennifer Nayak, division chief of pediatric infectious diseases at the University of Rochester Medical Center in New York. She was also “incredibly excited” by the Pfizer/BioNTech results.

“The fact that children are mounting a robust response to the vaccine is very positive and really bodes well that hopefully we’ll see the same thing as we move into the lower age groups in testing vaccines,” Nayak says.

With kids making up about 22 percent of the population in the United States, their immunity is crucial to reaching a national threshold of immunity, which experts estimate to range from 70 up to 90 percent, explains Tara C. Smith, an epidemiologist at Kent State University in Ohio.

Even if the U.S. reached that range without children, the disease would continue spreading because it’s herd immunity at the local, not national, level that matters, says Dominique Heinke, a postdoctoral researcher and epidemiologist in North Carolina. Even in a highly vaccinated population, unvaccinated people clustering together and interacting allows the virus to continue circulating, especially if they congregate indoors without masks and social distancing.

“That’s exactly what we see with kids’ social structures,” Heinke says. “Even if you’re at ‘herd immunity’ levels for adults, if the kids aren’t immune, either through natural immunity or through vaccination, then those chains of transmission aren’t getting broken and you’ve got a whole group of susceptible individuals where the virus can continue to transmit.”

The more transmission continues, the more the virus replicates and evolves, and the more opportunities it has to accrue mutations. “My biggest concern is the emergence of new variants,” Smith says. “We already have several here, and I’m concerned we’ll have more that could potentially escape immunity. I suspect we will see kids becoming a more prominent reservoir of this virus as more adults are protected by vaccination.”

Variants could keep the virus circulating

The variants that originated in South Africa (B.1.351) and Brazil (P.1), can infect people with immunity from previous infections, says Vaughn Cooper, a microbiologist and molecular geneticist at the University of Pittsburgh.

“That basically creates more chances for more infections in adults and more opportunities for transmission and subsequent evolution,” Cooper says. “To handle an evolutionary problem, you have to handle the number of evolutionary events. We’re not going to be able to stop that until we stop transmission among kids.”

Cooper also worries that the U.K. B.1.1.7 variant, which may be anywhere from 43 to 90 percent more contagious, and others like it will become the predominant viruses in the U.S. because they spread more easily. Since herd immunity is based on the reproduction number—the average number of infections that result from one infected person—a more contagious variant can also boost the level of herd immunity required to stop transmission, Smith says.

Unvaccinated and immune-compromised adults would therefore continue to be at risk for severe disease and death. And the risk is not zero for children either.

Kids left behind in vaccine trials

An estimated 3.4 million infections have occurred in children, according to the American Academy of Pediatrics, accounting for more than 13 percent of all U.S. cases. Children’s risk of death from COVID-19 is extraordinarily low—under 0.03 percent—and the most common complication, Multisystem Inflammatory Syndrome in Children is also rare, with just over 2,600 cases and 33 deaths through the end of February. But those numbers will increase as children make up an increasing proportion of infections.

Hence the frustration among some experts that it has taken so long to get pediatric vaccine trials running.

“What’s been hard from a pediatrician and a parent perspective is that we’ve been so excited about the COVID-19 vaccine and what this means for our lives, but really, we have left children out of that celebration and excitement,” Heard-Garris says, the attending pediatrician at Lurie Children’s in Chicago and assistant professor of pediatrics at Northwestern University Feinberg School of Medicine. “We’re a little late to the party. We should have thought about including kids from day one.”

In addition to their trial in adolescents, Pfizer is also testing their vaccine in 4,500 children ages 6 months to 11 years old. Moderna has an adolescent trial in progress and began recruiting  6,750 participants ages 6 months to 11 years old for another. AstraZeneca began a trial last month for those aged 6 to 17 years old, and Johnson & Johnson is planning a pediatric trial.

While there’s a good chance the FDA will authorize the Pfizer/BioNTech vaccine for that age group before school starts, results from the other trials aren’t likely until at least fall of 2021.

“What I’m worried about is that we are not going to roll these vaccines out fast enough to kids,” says Sallie Permar, chair of pediatrics at Weill Cornell Medicine and New York-Presbyterian Komansky Children’s Hospital. “We’re going to try to get them in their schools and their normal lives, which they need because we have a crisis on our hands in terms of mental health and obesity and all the things that came with social isolation and the shutdown. They may not be showing up with severe COVID disease, but they’re showing up with the symptoms of the social isolation in our health system.”

Weighing risks of social isolation against risk of disease

Returning to school before vaccines are available for all children means tough decisions for communities and families. Pediatric experts agree that returning to in-person school next fall must be a priority.

Joelle Simpson, interim division chief of emergency medicine at Children’s National in Washington, DC, says children need to be in classrooms next year whether or not they can get vaccines before school starts. She acknowledges how much researchers still don’t know about COVID-19 infections in children, including whether long-term effects are possible. But the evidence is clear regarding the negative impact on kids’ mental health, socialization, and development when they’re not in a school environment.

“We are certainly seeing an uptick in pretty severe mental health presentations as well as kids who have injuries from abuse, whether that be mental health or physical,” Simpsons says. “We have a school system that allows us to have trained eyes on kids to identify things like learning disorders, abuse and chronic conditions, which frankly cannot happen when they’re at home.”

Research has shown that wearing masks and maintaining three-feet distancing works well to prevent infections, Permar said. But questions remain regarding how well all schools can implement those measures and how officials will respond when infections occur.

“It would be amazing if every school had the resources they needed to be there five days a week and also offer virtual options for parents or caregivers that did not feel comfortable sending their kids back,” Heard-Garris says. “I don’t think that’ going to be a reality. If we see upticks in infection rates, then schools are going to go back the other way and kids will go back home, and that isolation and loneliness will get worse. If our children aren’t extended the vaccine or we don’t reach herd immunity, I worry those impacts are going to get bigger and bigger.”

Communities will need to strike a balance between the substantial benefits of in-person school and activities, and the risk of infection in that region and of individual populations, says Christopher Golden, an associate professor of pediatrics at Johns Hopkins University School of Medicine.

“We have not seen a spike in the number of kids that have had severe infections, but there are populations that may be at risk,” Golden says. “We’ve done a very important job of keeping people isolated and quarantined, but we still have seen that African American and Latino children and children with chronic medical conditions are at higher risk, so if we do open things back up again, there is the possibility that infections could increase and be more severe in at-risk populations.”

Inequities in vaccine distribution could worsen disparities

Even when pediatric vaccines do become available, disparities in some of these vulnerable populations may increase.

“It’s troubling,” Heard-Garris says, because many cities already are not equitably distributing vaccines to the racial and ethnic minority populations at highest risk. “One of the things we worry about when we talk about equity is that you can widen disparities inadvertently by offering certain interventions, such as offering a vaccine that a large population either can’t get or has concerns about.”

Experts also worry about vaccine hesitancy among parents, especially since no previous vaccine approved for kids older than toddlers has achieved coverage rates of more than 50 percent, Permar says. The longer it takes for vaccines to become available for children, the longer it will take to address that hesitancy and ultimately vaccinate enough children to make headway toward herd immunity.

“This virus isn’t going away, ever, but I think the pandemic, the mess that we’re in right now, it will have a very long and painful tail—many years—if we don’t vaccinate kids,” Cooper says.

o until widespread vaccination in kids returns them to normal classrooms, the rest of the country won’t be returning to true normal either.

“We’ll still have to have a lot of mitigation measures in place,” Heinke says. “It’s still going to be a matter of wearing masks, remaining distanced, probably limitations on the number of people in buildings and ventilation still being very important. To some extent, individuals will be able to live in a more normal existence if they’re vaccinated, but the whole society won’t be able to go back without vaccinating children.”

Why kids need their own COVID-19 vaccine trials

(Updated 4/3/2021)

Adolescents are being tested now. Younger children will be next. Why did vaccine manufacturers wait to study them?

In January, Megan Egbert saw a post on her Facebook feed that COVID-19 vaccine manufacturer Moderna was recruiting volunteers for a clinical trial in adolescents. She quickly thought about her two daughters, ages 14 and 12.

Like most teenagers, the girls had been through a tough year of remote learning and missed activities. Egbert, a librarian from Boise, Idaho, hoped that participating in the clinical trial was a way for her daughters to get access to the vaccine, which so far has been authorized for use only in adults. (The Moderna vaccine is cleared for ages 18 and older; the age cutoff for the other vaccine authorized in the U.S., from Pfizer-BioNTech, is 16.)

Her daughters were taller than most adults, so she didn’t think they would be at risk to take the regular-size dose that was being tested. The girls quickly agreed to the idea; a few weeks later, they received their first shot, with a two-in-three chance that it was the real vaccine instead of a placebo.

A local television station interviewed the sisters, who had become “mini celebrities” at school for participating in the trial, says Egbert. The next day, she checked the link to the news report on Facebook and found hundreds of comments. While some hailed the sisters as “brave young ladies,” others questioned their parents’ judgment.

“People were saying we were using our kids as guinea pigs,” says Egbert. “They were saying it’s not for teens until it’s been tested.” But that raises a long-standing quandary of pediatric medicine: How can scientists know the vaccines are safe for children unless they test them on actual children? And if children can benefit from the vaccine and play an important role is establishing herd immunity, why have pharmaceutical companies waited to study them?

Different immune systems

The U.S. Food and Drug Administration requires that new vaccines be independently studied in children. Children’s immune systems are still maturing and are unpredictable, so they might react to the coronavirus differently or have side effects that don’t occur in adults.

“They might respond better or worse,” says James Campbell, professor of pediatrics at the University of Maryland School of Medicine’s Center for Vaccine Development and Global Health. “Until you do the study with the vaccine, you don’t know what will happen.”

Despite early perceptions that the pandemic has largely spared U.S. children, the cumulative data reveal a different story. As of February 11, up to 2.3 percent of the more than three million children who have tested positive for COVID-19 were hospitalized, and at least 241 children have died.

While vaccination can protect children from becoming infected with—and spreading—COVID-19, pediatricians also hope that it will prevent a dangerous and rare disorder known as Multisystem Inflammatory Syndrome in Children, which has been documented in coronavirus patients. The disorder can involve inflammation in several vital body parts, including the heart, lungs, and brain.

“I’m seeing these inflammatory conditions constantly in the hospital and am worried,” says Joseph Domachowske, professor of pediatrics at State University of New York Upstate University in Syracuse. “If we can prevent the onset of the infection itself, we can prevent the post-infection consequences.”

Last fall, the influential American Academy of Pediatricians called for children to be included in COVID-19 vaccine trials, and many parents are eagerly waiting to see if vaccinations will be available before the start of the school year.

Several trials of COVID-19 vaccines involving adolescents are already underway. Pfizer-BioNTech is testing its coronavirus vaccine on 2,259 children between 12 and 15. Moderna is enrolling 3,000 participants ages 12 to 17, and Johnson & Johnson has said it will launch a similar trial if its vaccine candidate receives emergency authorization from the FDA.

The initial vaccine data for the adolescent groups could come as early as the summer. Data for younger children could be available the following year. Once that data is in, the companies will conduct additional trials with children as young as six months.

Building on adult results

Despite the urgency, Campbell says the staggered approach is a prudent one for COVID-19 vaccines, because children aren’t in the highest risk group. One recent Icelandic study of 40,000 people found that children under 15 were half as likely to get the coronavirus as adults and half as likely to spread it.

So-called “age de-escalation” is a common strategy in drug development, especially when a disease is more severe in adults, according to Campbell. For example, he’s studying a universal influenza vaccine that was tested in adults first and yielded promising results. Now he’s starting trials with children in three staggered age groups so he can compare the side effects, dosage levels, and immune responses.

One advantage of studying adolescents immediately after adults is that researchers can build on the track record of adult volunteers. During the FDA review process of the Pfizer-BioNTech vaccine in December, the agency looked at data from 21,720 people who’d taken the vaccine as part of the phase three study. That data clearly showed that the vaccine is 94-percent effective at preventing COVID-19.

“We don’t need more efficacy data,” says Robert Frenck, director of the Vaccine Research Center at Cincinnati Children’s Hospital, who’s also the principal investigator for the Pfizer-BioNTech vaccine trial there. “We know it’s 94 percent. We think the immune response will translate.”

That’s why investigators are studying a far smaller number of adolescents to evaluate vaccine safety and validate the adult results. The concept is known as an immunological bridge: Since they know the vaccine’s efficacy from adult trials,  they simply need to evaluate whether adolescents who received the vaccine also successfully produce antibodies to ward off future COVID-19 infections.

It also makes sense to target adolescents first, since they’re more likely to get infected than their younger peers. In one review of pediatric COVID-19 cases, children ages 12 to 17 made up 63 percent of cases, while children five to 11 accounted for just 37 percent.

Because children’s immune systems develop over time, evaluating COVID-19 vaccines in younger children will require a new strategy altogether to see if they need a different formulation or dosage, says Domachowske, who’s supervising pediatric trials for Pfizer-BioNTech at SUNY Upstate University.

“Children are most certainly not just small adults,” he says. Although children reach adult-like levels of immunity by age six, that pace differs from child to child based on genetics and environment.  

In the Pfizer-BioNTech trial of children ages five to 11, which could begin as early as March, those participants will start off with a lower dose than the amount currently given to adults and adolescents. “It’s just to see side effects and demonstrate that they have a protective immune response,” Domachowske says. “Then, if needed, we try the next higher dose to see if that’s acceptable and to determine if the vaccine has a safety and efficacy profile that’s similar to adults.”

Next phases will include children as young as two years, and then for babies down to six months. Depending on the results, the vaccine makers could end up producing a different dose for younger children.

Domachowske said pediatricians often gave half the amount of a typical flu vaccine shot to children from six months to three years out of an abundance of caution, but recently started giving the full dosage after new data showed the full amount was tolerated just as well and even produced an equal—or better—antibody response.

Research reckoning

This careful approach to pediatric research is a welcome contrast to the period from the 1900s until the 1970s, when some children were subjected to abuse in the name of medical progress, says Douglas Diekema, director of education for the Treuman Katz Center for Pediatric Bioethics at Seattle Children’s Hospital.

“Few people know about the kids in institutions that were involved in egregious research,” he says.

Take these shocking examples: In 1949, dozens of boys at the now-closed Fernald State School in Massachusetts were fed oatmeal laced with radioactive tracers as part of an experiment to see how nutrients traveled throughout the body. Another 14-year study started in 1956 at Willowbrook State School, a home for children with cognitive disabilities in Staten Island, New York. There, healthy children were purposely fed live hepatitis virus from stool samples of sick children to see if they would become ill.

Following widespread reforms in the 1970s, all research with human subjects must go through a hospital’s institutional review board. Children are also now specifically protected under legislation created in 1983, adds Liza-Marie Johnson, chair of the Hospital Ethics Committee at St. Jude Children’s Research Hospital in Memphis, Tennessee.

“Some people have wondered why kids weren’t enrolled in COVID-19 trials earlier, but the purpose of these regulations is to protect kids from unnecessary risk,” says Johnson. For instance, children were enrolled only when there was enough data about the vaccines’ safety in adults. “Research is opened to minors when a trial is low risk and offers potential for benefit.”

However, researchers routinely struggle with convincing parents to enroll their children in pediatric trials. Not surprisingly, successful recruitment is directly related to how sick a child is. “Parents are extremely motivated to participate if their child has a rare disease,” says Erica Denhoff, education program manager of Institutional Centers for Clinical and Translational Research at Boston Children’s Hospital. “Oftentimes this drug might be their only hope whether their child survives or has a chance of having a normal life.”

Getting kids into trials becomes much more challenging if they’re not in immediate danger, and participation requires frequent appointments or monitoring. Parents are more likely to opt out if a study has rigid hours, or they’re juggling child-care or transportation issues, she says.

Even joining COVID-19 vaccine trials requires a significant commitment. Egbert says that for the Moderna study, her daughters had to agree to keep symptom diaries for a week following both injections, attend regular telemedicine visits, and submit to four coronavirus tests and four blood draws over 13 months. “I tell them this is like a job,” she says, adding that they will each be compensated $1600 by Moderna, paid in increments, as long as they stay in the trial.

A sense of purpose

The most effective way to enroll and retain study participants is to help them form an emotional connection to the trial’s purpose, says Tricia Barrett, senior vice president and managing director at Praxis Communications, a clinical trial recruitment firm.

“There’s a big sense of altruism. Parents think, I’m not only helping my child, but others as well,” she says. “For the kids, we help make them feel like part of something cool.” 

Bob McDonnell is one of the nearly two million legendary “polio pioneers,” whose participation in the Salk trials helped stop the spread of the paralyzing disease. At age nine, he didn’t have much say in participating. But as a 76-year-old retiree in Loveland, Colorado, he’s grown more grateful of his role over time. “Now I’m glad I was part of something for the good of mankind,” he says.

Charles and Lara Mashek of Oklahoma City also considered the practical and magnanimous implications when they signed up their daughters, ages 14 and 12, in the Moderna trial at the Lynn Health Science Institute. Both physicians, they’d already been immunized against COVID-19 and were eager for their kids to have a chance at getting the shot. “We believe strongly in vaccines, and we see the value of testing and trials,” says Charles Mashek.

Will COVID-19 cancel your family reunion?

As vaccines roll out, traveling to gather with relatives is possible this summer. Here’s how to keep it small and safer.

(Update 5/8/2021)

Carmelita Brown, 77, has been painstakingly careful with her health over the past year, even after being fully vaccinated against COVID-19. “I’m older and African American, so I’m higher risk,” she says. When she recently flew from her home in Florida to Montana for her goddaughter’s wedding, she donned three masks and a face shield on the plane.

The 20-person, mostly outdoor affair was such a trouble-free experience that Brown is now itching to plan a summer trip with her kids and grandkids. Among the group vacations being discussed: a Mexican getaway; an Alaskan cruise (a do-over for a 2020 trip that was canceled); or, says Brown,“I was thinking Vancouver or Victoria, but the Canadian border is still shut.”

Like Brown, many Americans are anxious to reunite with family this summer after months of lockdowns and delayed trips. Travel advisor Suzy Schreiner of Azure Blue Vacations is dubbing 2021 the year of the rendezvous. “Almost everybody has a group they’re traveling with,” she says.

In a second summer of COVID-19, planning a family reunion of any kind requires working through thorny details. “There’s pent-up demand and interest, but still a great deal of caution,” says Rainer Jenss, founder of the Family Travel Association. Certain kinds of trips that would have appealed before—big-ship cruises, dozens-of-cousins resort meetups—are mostly out, researching restaurants near your destination with curbside pickup is in. Here’s what to consider as you plan a family reunion.

Stay healthy in a group

No matter where travelers go, they can’t escape COVID-19 risks. That means safety protocols have to be part of your itinerary, says Joshua K. Schaffzin, director of Infection Control & Prevention at the Cincinnati Children’s Hospital Medical Center. He encourages families to have honest conversations ahead of time about how they’ll handle various scenarios, like if rain washes out a scheduled outdoor dinner.

Having a fully vaccinated group makes these choices much simpler, notes Lucy McBride, an internal medicine physician in Washington, D.C., who writes a weekly COVID-19 newsletter. “Then the risk is close to zero,” she says. The U.S. Food and Drug Administration appears poised to approve the Pfizer-BioNTech vaccine for children as young as 12 years old this week. But even unvaccinated kids get a large degree of protection when interacting with fully inoculated family and friends. 

En route to destinations and when participating in activities with unjabbed folks, families need to keep following virus safety protocols (masks, social distancing, hand washing), particularly in potentially crowded locations such as airports, restaurants, and tourist attractions.

For example, McBride’s unvaccinated niece and nephew will be part of her family’s hiking and fishing vacation this summer. Although she’s not worried about spending time with the children indoors, they’ll need to get tested before the trip to make sure they’re not bringing an infection with them. “And I wouldn’t want them to go out in public without a mask,” she says.

Not sure which rules make sense for your group? If you’re mixing unvaccinated people from several different households, McBride suggests talking it out with a doctor. Expect a rubric of choices rather than a definitive reply—there’s no magical maximum group size or list of approved activities. Instead, it’s a matter of balancing multiple factors. “People want to be told yes or no. The answer is it depends,” she says. “You have to know what your risks are and your risk tolerance.” 

Schaffzin notes that new variants or spikes in cases could pop up at any time. “So it’s completely reasonable to make plans, but pay attention to the numbers.” If hospitals are filling up near your destination, that’s probably not the best time to go. 

Where to go and when to book

Thinking of renting a beach house in a classic family destination like North Carolina’s Outer Banks or road tripping to a national park? Book reservations soon.

“It’s not just you. Everybody has the same idea,” says Sally Black, founder of Vacation Kids and author of Fearless Family Vacations: Make Everyone Happy Without Losing Your Mind. Her travel agency has been fielding multiple similar requests for groups of a dozen or fewer people interested in outdoor activities. Many families want to check out dude ranches, a trend Black appreciates. “I love cowboys,” she says. “It’s like luxury camping—get outdoorsy without a tent.” But availability is always tricky, and this year, it’s practically impossible. She’s already booking family ranch trips for summer 2022.

According to Vrbo data, optimistic families started snagging vacation rental houses months earlier than normal, and they’ve booked extra-long stays.

Anywhere close to famous natural wonders will likely be teeming with visitors and caravans of RVs. Yosemite National Park is requiring reservations to enter this summer, one of many strategies the National Park Service is using to protect popular sites from overcrowding.

Black says to stay flexible and prepare for some sticker shock, since the surge of interest in outdoor adventures means there are fewer deals. Refundable options also tend to cost more, but are wise given the uncertainty of, well, everything.

What about cruises and international trips?

Several kinds of travel that were impossible for much of 2020 are now on the table. Long-neglected American passports may soon be welcome again in Europe—for those who flash their vaccination cards. Cruise ships, which have been under do-not-sail orders since spring of 2020, have gotten the green light from the CDC to resume U.S. operations by mid-summer as long as 95 percent of customers and 98 percent of crew have been vaccinated. (McBride thinks this could be a good way to incentivize people who are vaccine hesitant to get their shots.)

These developments are welcome news to many people, especially those hoping to be among the first tourists back in places that had mostly shut down to outsiders. But Jenss doesn’t expect that everyone will rush into faraway meet-ups. “The wild card is how safe families feel about leaving the country and being let back in,” he says. 

Nearby countries (Costa RicaMexico) or a Caribbean island might seem less daunting, Jenss says. While these places have remained open to visitors for much of the pandemic, they aren’t necessarily safer than other international destinations. The U.S. State Department and the CDC both recommend not going to Mexico, where COVID-19 caseloads remain high and vaccination efforts are slow.

The longer you can hold off on international travel the better, advises Schaffzin, because more COVID-19 research and more vaccinations will eventually make the world safer. His far-flung clan is subbing monthly Zoom for an in-person gathering this year. Dozens of Brown’s relatives who usually meet every other summer in a different U.S. city are postponing their reunion, too. “We have a committee, and it voted that we can’t get together until everyone is vaccinated,” she says.

As long as she can see her closest relatives now, Brown says the bigger plans—and bigger reunions—can wait until 2022.

Yes, vaccines block most transmission of COVID-19

(Update 4/23/2021)

The latest data show that getting a shot not only protects vaccinated individuals, it reduces the chance they can spread the virus to others.

COVID-19 vaccines have provided an opportunity to slow the spread of the virus and end the pandemic. Now scientists are trying to learn just how much the vaccines can prevent transmission from occurring at all. New data from the CDC shows that COVID-19 infections do occur in vaccinated people, but they appear exceptionally rare.

As of April 14, the Centers for Disease Control and Prevention had received reports that 5,814 fully vaccinated people had developed COVID-19 infections. Nearly half of these infections (45 percent) were in people at least 60 years old. Seven percent of people with breakthrough infections—infections that occur after complete vaccination—were hospitalized and one percent died.

With more than 85 million people in the United States fully vaccinated against COVID-19, the CDC has been cautiously expanding guidelines about what those fully vaccinated people can safely do. The expansion has been gradual as experts awaited data on not just how well the COVID-19 vaccines prevent disease, but also whether a fully vaccinated individual could develop an infection—without symptoms—and unknowingly pass the virus along to someone else.

The distinction is important because many people do not realize that vaccines primarily prevent the disease but not necessarily infection. That means not all vaccines block fully vaccinated people from transmitting the pathogen to others.

“The holy grail of vaccine development always is to stop people from ever getting infected, but it is monumentally difficult to get that,” says Jason Kindrachuk, an assistant professor of virology at the University of Manitoba in Winnipeg, Canada. That holy grail is called sterilizing immunity, completely protecting a person from disease as well as stopping the microbe from getting into cells in the first place, he says.

Four months after the Food and Drug Administration authorized the first vaccines against COVID-19, the CDC has enough data to suggest the vaccines substantially reduce infections—and therefore reduce the possibility of a vaccinated person infecting others.

How vaccines protect people

Vaccines work by mimicking an infection in the body to trick the immune system into mounting a defense against it—and then remembering what to do if they see the same pathogen again, explains Juliet Morrison, an assistant professor of microbiology at the University of California, Riverside.

After any infection, “you have white blood cells, specifically T and B cells, that hang around and remember that initial infection so that if you do become infected again, these memory cells respond by immediately multiplying their numbers,” she says. The B cells produce antibodies that bind to circulating viruses and infected cells while T cells “basically punch holes in the infected cell and pump them full of these toxins that tell the infected cell to commit suicide.”

A vaccine induces the same immune memory as an infection so if the real virus comes along, the immune system switches on immediately and produces T cells, B cells, and antibodies.

“That will allow you to clear the infection without you even recognizing that you’ve gotten sick,” Morrison says.

What’s key, however, is that you did actually have an infection. That is, the virus entered cells and began replicating. The immune system simply shut it all down before the virus or the immune system itself began damaging tissue—the disease process, explains Kindrachuk.

Asymptomatic infections can still transmit the virus

If the virus enters cells and begins replicating but never causes disease, that’s an asymptomatic infection. With presymptomatic infections, on the other hand, a person goes on to develop symptoms and is especially contagious in the days before symptoms appear, says Natalie Dean, an assistant professor of biostatistics at the University of Florida in Gainesville.

“We know from contact tracing data unrelated to vaccines that people who never develop symptoms tend to be less infectious,” Dean says.

Morrison adds that asymptomatic people probably have an excellent initial immune response to slow down how quickly the virus can copy itself, “but not enough that viral replication is completely shut off,” she says. “That’s why they could still shed virus but we’re not seeing any disease symptoms.”

Supporting that idea is the fact that the severity of COVID-19 disease tends to correlate with the total number of viruses in the body, called viral load, Kindrachuk says. Early research showed that people with lower viral loads transmit less virus, further suggesting that asymptomatic infections are less contagious than symptomatic ones. But less is not zero: People with asymptomatic infections still have replicating viruses in their system that they can transmit to others.

When the vaccines were authorized, experts did not yet know whether the shots could prevent infections entirely or whether vaccinated people could develop an asymptomatic—but still contagious—infection.

Why didn’t clinical trials track infections? 

The clinical trials testing vaccines from Moderna, Pfizer-BioNTech, and Johnson & Johnson measured each vaccine’s ability to prevent serious disease, not its ability to block transmission of the virus.

“Frankly, transmission wasn’t the primary concern at that point of the trials,” Kindrachuk says. “It was to make sure people weren’t getting sick.”

With thousands of people being hospitalized and dying every day, the first priority was to measure whether a vaccine prevented severe disease and death. While researchers recognized that it was important to measure whether vaccines prevented asymptomatic infection, doing that was very difficult and costly, Dean says. So researchers tracked symptomatic infections instead. That left unanswered the question of whether any vaccinated people without symptoms could have an asymptomatic infection.

“There were some questions about whether you could still have virus in your nose and still be infectious,” Dean says.

Even a tiny amount of virus in a vaccinated person might present a risk to others.

“We don’t have a good idea of what the infectious dose is for somebody—how much virus you have to be exposed to to get infected,” Kindrachuk says. “It’s not about the one dose you get in a single moment, but the accumulation over minutes to hours.”

Early data looked promising

Although the vaccine manufacturers did not track infections for all phase three trial participants, they did gather some data. Moderna tested all participants when they received their second dose and reported in December that fewer asymptomatic infections occurred in the vaccinated group than the placebo group after the first dose. Johnson & Johnson also reported data from nearly 3,000 phase three trial participants who were tested two months after vaccination to see if they had antibodies from a new infection since vaccination. That preliminary data suggested a 74 percent reduction in asymptomatic infection.

Those findings hinted that the vaccines had the ability to prevent infections. That development was followed by three preprints—not yet peer-reviewed—that suggested even more good news. One found that people vaccinated with one dose of the Pfizer-BioNTech vaccine had viral loads up to 20 times lower than viral loads in unvaccinated, infected people.

Two others, from the Mayo Clinic and the U.K., included more than 85,000 routinely tested healthcare workers who were fully vaccinated with the Pfizer-BioNTech vaccine. The vaccine reduced infection by 85 to 89 percent. All this evidence underscores all three vaccines’ ability to prevent infection in the majority of those vaccinated.

A consensus begins to emerge

More evidence accumulated in March with a slew of studies about the mRNA vaccines. One with 9,109 healthcare workers in Israel found infections cut by 75 percent after two doses of the Pfize-BioNTech vaccine. Another revealed that the viral load fell fourfold in those who received one dose and then developed an infection.

Among more than 39,000 people screened for infection at the Mayo Clinic, patients had a 72 percent lower risk of infection 10 days after the first dose of either mRNA vaccine and 80 percent lower after both doses. The New England Journal of Medicine published research letters showing reduced infections in fully vaccinated healthcare workers at the University of Texas Southwestern Medical Center, the Hadassah Hebrew University Medical Center in Jerusalem, and the University of California in Los Angeles and San Diego.

The most persuasive evidence, according to Dean, came from an early April CDC study of 3,950 healthcare workers who were tested weekly for three months after receiving both doses of either mRNA vaccine. Full vaccination reduced infection—regardless of symptoms—by 90 percent, and a single dose reduced infection by 80 percent.

Then there’s the evidence all around us, Kindrachuk says.

“We’ve seen a pretty drastic decrease of transmission in the country,” he says. “That suggests not only are the vaccines protecting against severe disease but it suggests there’s a reduction in transmission.”

Taken together, the evidence shows that full vaccination with either mRNA vaccine cuts risk of infection by at least half after one dose, and by 75 to 90 percent two weeks after the second dose. Though less research is available on the Johnson & Johnson vaccine, the trial data suggest an infection reduction of more than 70 percent is likely. With the vaccines preventing this much infection, they’re also stopping the majority of vaccinated people from passing along the virus.

Along come the variants

The concern now is how much the variants might change the game, Kindrachuk says. Several of the studies from England and Israel with the Pfizer-BioNTech vaccine occurred when the B.1.1.7 variant was dominant.

“The vaccines seem to be holding their own against the variants, but we also know that these variants tend to be more transmissible,” Kindrachuk says. One concern is that greater transmissibility could mean it takes a lower dose to get infected, he says.

Since the vaccines don’t block 100 percent of infections, it’s possible that vaccinated people who develop an asymptomatic infection from that variant could be more contagious than they would have been before with the strain dominant since early in the pandemic.

Further, there isn’t as much data for the Moderna or Johnson & Johnson vaccines against B.1.1.7 infections, and virtually no data on infections from the other two variants of concern, B.1.351 from South Africa and P.1 from Brazil, both of which have shown some ability to evade antibodies against other variants of the COVID-19 virus.

Scientists are also studying how well the variants replicate.

“If they’re replicating to higher levels, then there could be more viral shedding and more opportunity for transmission,” Morrison says.

The future still looks bright 

Despite the uncertainty posed by the variants, the overall picture right now is reassuring, Dean says.

“These vaccines have really exceeded expectations in so many ways, and it’s just an enormous value that they can keep you from getting sick but also keep you from transmitting to others,” she says. “Nothing is 100 percent, but I think people can understand the big reduction and the value of that. It changes how I think about what I want to do in a big way.”

But that doesn’t mean throwing caution to the wind, Morrison says.

“If you’re vaccinated, you can pretty much assume that you are protected against severe disease and very likely protected against enough infection to transmit, but because we have these variants emerging and the fact that we’re not even close to herd immunity, people should still be taking precautions,” Morrison says.

Interacting with other vaccinated people without masks makes sense, but she also agrees with the CDC recommendation for vaccinated people to visit without masks or social distancing only with low-risk unvaccinated people in a single household. With so many infections still occurring daily, that limitation further reduces the likelihood of vaccinated people picking up and spreading infections from an unvaccinated home.

“The real worry is for the unvaccinated people you come into contact with,” she adds. “Even if the potential for them to pass it on to you is low, it’s not zero.” Similarly, an infected vaccinated person has lower—but not a zero—likelihood of infecting others who aren’t vaccinated or have conditions or medications suppressing their immune systems.

The more vaccinations increase, the more everyone’s risk of infection drops, Dean says.

“I still think about how much transmission is ongoing in my community,” Dean says. “We’re starting to see the population level impact of vaccines, but every single person vaccinated adds up to feeling safer about getting together.”

Future COVID-19 vaccines might not have to be kept so cold

(Update 53/2021)

The action was innocent: While cleaning the Veterans Affairs hospital in Boston this past January, a contractor knocked a loose freezer plug from its socket. This simple mistake resulted in the loss of nearly 2,000 doses of Moderna’s COVID-19 vaccine that had been chilling inside the unplugged appliance. While that’s a small hit on the grand scale of worldwide vaccination, it’s emblematic of a much larger issue for many COVID-19 vaccines; they have to be kept frozen.

Two of the major coronavirus shots authorized for emergency use in the United States—the Moderna and the Pfizer/BioNTech vaccines—rely on a costly series of temperature-controlled shipments and storage, known as the cold chain, to get vaccines from manufacturers to muscle injection. Such stringent temperature requirements also pose an obstacle for equitable vaccine distribution, increasing the cost and difficulty of shipments and cutting off access to remote communities without reliable electricity or refrigeration.

The reason for these frigid conditions is that the key vaccine ingredient—a molecule called messenger RNA (mRNA)—is extremely fragile and storage at cold temperatures slows down the chemical reactions that can tear it apart. But promising efforts to reduce this frosty burden are already in the works—from tinkering with the mRNA structure to shipping the vaccine in solid form with a sugary protectant.

Such efforts are not just important for halting the current pandemic. Scientists see promise in mRNA vaccines for treating a wide variety of other diseases, since they can be readily tweaked for different viral variants as well as rapidly developed for new viruses.

“All those steps that are taken now will be really important in the coming years,” says Rein Verbeke, a pharmaceutical scientist specializing in mRNA vaccines at Ghent University in Belgium.

Self-destructing molecules

The necessity for cold storage lies at the heart of how these vaccines work, which is mRNA. These strands of genetic code in the COVID-19 vaccine carry instructions that the human cell uses to manufacture the characteristic spike protein, which sits on the surface of SARS-CoV-2. This preview of the protein familiarizes the body’s immune system with the virus so that it can recognize and fight future coronavirus invaders.

Messenger RNA is similar to a single strand of DNA, but its backbone carries one crucial difference: an additional chemical group made up of oxygen and hydrogen, known as hydroxyl.

If the RNA strand bends in just the right way, this hydroxyl group can interact with another part of the backbone sparking a reaction that severs the genetic chain, explains Hannah Wayment-Steele, a PhD student studying RNA structure at Stanford University.

“It cuts the message off,” she says. And these shortened messages cannot build a complete protein. “Only one cut in your mRNA strand can be enough to lose your function,” says Verbeke, the pharmaceutical scientist.

To slow degradation, companies keep the vaccines at low temperatures. The lower the temperatures, the slower the molecular movements—and the lower the chance of damaging reactions, Verbeke explains. The Pfizer/BioNtech vaccine must be shipped at temperatures colder than nearly 80 degrees below zero. It can be stored for up to two weeks in a standard freezer, up to five days in a fridge, and only six hours at room temperature. Moderna’s vaccine is slightly more forgiving. It is stable for up to six months in a standard freezer, up to 30 days if refrigerated, and 12 hours at room temperature.

Vaccine storage is further complicated by another key component: fat. In both the Pfizer/BioNTech and Moderna vaccines the mRNA is encased in fat bubbles known as lipid nanoparticles. They serve as a delivery vehicle to shuttle the mRNA into cells where the cellular machinery can get to work producing the encoded spike protein.

Lipid nanoparticles also help with mRNA stability by shielding it from RNA-degrading enzymes that are abundant both within our bodies and throughout the environment. Yet over time, the lipid nanoparticles themselves can degrade or aggregate, and for a vaccine to work the structure of both fats and mRNA must be injected intact. “It’s a difficult thing to accomplish,” Verbeke says.

Genetic origami

Some natural forms of RNA can survive within our bodies for more than 12 hours, says Rhiju Das, a computational biochemist at Stanford University. “They’re these proofs of concept that the RNA should be able to last longer than it does in those vaccines,” he says. And one thing these robust RNA molecules have in common are intricate structures that constrict the strand and prevent it from bending in a way in which it can cut itself in two.

“Industry folks had tried using a lot of other things,” Das says. They tried tweaking the lipid formulas. They shifted the acidity of solutions. “They couldn’t find a way to solve it,” he says. But one avenue that was largely unexplored was these intricate folded RNA structures.

This is a potentially useful strategy for vaccine development because multiple mRNA sequences can code for the same protein—and each crumples up in a different way. So if scientists can identify the sequence that folds into the most stable shape, they can produce a vaccine with less stringent temperature requirements for shipping and storage.

The trick, however, is identifying the best genetic origami. “You have these astronomical numbers of possible sequences,” says Wayment-Steele, which leads to “whole galaxies of structures that a molecule could take.” To narrow the possibilities, Wayment-Steele and her colleagues turned to an online game known as Eterna, which harnesses the power of crowds to assist in RNA design through puzzles.

Das and his colleague Adrien Treuille of Carnegie Mellon developed the game about a decade ago when they kept running into problems that AI couldn’t solve. “Almost out of desperation we decided to try this sort of crowdsourcing approach,” says Das, who is Wayment-Steele’s graduate advisor. “Eterna’s ended up solving hard problem after hard problem.”

Eterna users switch out units of the genetic code, called bases, and the game predicts the folded shape and estimates its stability. “Sometimes it will cause the whole [mRNA] structure to change by changing just that one base,” says Amy Barish, a retired chemist and an Eterna player in Cumming, GA. The scientists then work with the players to develop AI, using their structures as examples to train a computer to predict the most stable RNA forms.

Through their work with Eterna players, the team developed a series of mRNA sequences that encode for the spike protein of SARS-CoV-2 variants B.1.351, P.1, and B.1.1.7, first identified in South Africa, Brazil, and the United Kingdom, respectively, that are potentially twice as stable as conventionally designed sequences. They are freely available online for vaccine developers, Das notes.

“It’s just great that we can work on this fun, challenging game but yet we’re potentially helping the world,” says Barish, who worked on some of the spike protein puzzles.

Much more work is required, however, before these so-called “superfolder” mRNAs can be injected into arms. One previous concern is that their structure would hinder cellular machinery, known as ribosomes, from reading and translating the mRNA instructions into proteins, explains Maria Barna, a geneticist at Stanford University. She teamed up with Das’ lab to test superfolders’ translation using mRNA that codes for a set of easily analyzed proteins, including one that fluoresces green. They were surprised and delighted to find that ribosomes could not only unwind the superfolder structures to produce lots of protein, but the superfolders actually generated more protein than the less stable RNA structures.

“These superfolder mRNAs are not just a dream, they can actually work, and they work well—more than we would have expected,” Barna says.

Exactly how this will translate to COVID-19 vaccine stability remains uncertain, but Barna says they hope to produce vaccines that can be stored at room temperature for weeks at a time, if not longer. The team is now collaborating with a pharmaceutical company to test the superfolder spike protein structures in real world applications.

Drying it down

Another possibility for stabilizing the vaccines is drying or freeze drying so they can be stored at room temperature in solid form. But removing the water while keeping the RNA structure intact is no small feat. As the liquid freezes, the crystallizing ice can crush the molecule while whisking away water that can lead to structural collapse.

One way to avoid this damage is through the addition of sugar. Carlos Filipe, chemical engineer at McMaster University, and his colleagues have been testing sugary recipes for drying vaccines, and their current formulation relies on two different types of sugar—trehalose and pullulan.

Trehalose helps fill the voids in the molecule as the water dries away, acting like scaffolding to prop up the structure. The sugar pullulan, which is the base of Listerine strips, encapsulates the molecule to keep it from twisting, which prevents the backbone from cutting itself apart.

“It’s like Hans Solo when he was in the carbonite,” says Filipe, posing frozen like the fictional Star Wars character with his hands held up, mouth agape.

Before the COVID-19 pandemic the team demonstrated the efficacy of this sugar treatment to dry out vaccines for the Herpes Simplex type 2 virus and the Influenza A virus and then tested the reconstituted vaccines in mice. Along with his colleague Robert DeWitte, Filipe co-founded the company Elarex to bring this technology to market. They’re now working to test the mixture for drying mRNA encapsulated in lipid nanoparticles.

There are multiple different sugar combinations that might work, notes Daan Crommelin, a pharmaceutical scientist at Utrecht University, Netherlands. Yet even with sugar, drying may still have its challenges. For one, drying vaccines could increase the time and cost of production, Crommelin notes. But such costs could be greatly offset by elimination of the cold chain, says DeWitte, who is CEO of Elarex.

Most importantly, there are many options to investigate, or as Crommelin says, “There are several ways that lead to Rome.” But he notes the old adage needs a tweak in this case since it’s likely not just one road or another. A combination of efforts will be required to distribute COVID-19 vaccines to people no matter where they are in the world.

The next wave of vaccines

Versions of a more stable mRNA vaccine for COVID-19 seem to be on the horizon. Pfizer and BioNTech are currently recruiting participants for a phase 3 trial that will evaluate a freeze-dried version of their SARS-CoV-2 vaccine. They hope for results in the second half of 2021, after which they can submit the results to regulatory agencies for review.

Other companies also have new versions of a liquid mRNA COVID-19 vaccine that may be refrigerator rather than freezer stable. But scant details are available on the reasons behind the stability. Moderna initiated a Phase 1 trial for a version of their next-gen COVID-19 vaccine that they say is refrigerator stable. But after repeated requests the company did not answer questions about reasons behind stability of the new formulation.

The German company Curevac also claims its vaccine is stable in a refrigerator for up to six months and at room temperature for 24 hours. Similar to other vaccines on the market, Curevac’s is encapsulated in lipid nanoparticles (LNPs) and must be protected from cutting itself apart. “We think we might have achieved this by having the mRNA tightly packed within the LNP,” company spokesperson Thorsten Schüller wrote in an emailed statement to National Geographic. “Our theory is that the more compactly the mRNA is packaged, the less attack surface there is.” When pressed for details the company responded: “it is hard to pin down differences in stability to just one aspect.”

Still, the diversity of possibilities is an encouraging sign of potential improvements to mRNA vaccines already on the market. “This feat was tremendous,” Verbeke says of the speedy delivery of a safe and effective vaccine against COVID-19. 

Why annual COVID-19 boosters may become the norm

(Update 4/16/2021)

Even as tens of millions of inoculated Americans breathe a collective sigh of relief after receiving either the one or two-dose COVID-19 vaccine, some wonder whether one round of shots is enough, or if they’ll need another—and another.

Scientists don’t yet know how long protection from the current cohort of coronavirus vaccines will last. Since the discovery of the original strain in late 2019, the virus has continued to mutate, yielding variants—similar-but-distinctive versions of the virus with the potential to be more infectious, deadly, and escape the antibody safeguards provided by the existing COVID-19 vaccines. To stay ahead of virus evolution, some vaccine creators are racing to design new shots to beat back variants while working to determine how long immunity lasts from current doses.

And the new “normal,” some experts say, could mean routine inoculation, or boosters, against COVID-19.

What’s a booster, anyway?

A booster shot is “a repeat dose of a vaccine that you’ve already received to literally boost your immunity,” says Susan R. Bailey, an allergist and clinical immunologist and president of the American Medical Association. The immune system creates virus-fighting memory from repeat exposure. It’s common that a second or third encounter with an antigen, a molecule that prompts antibody production, creates a “greater and more long lasting” immune response, Bailey says.

The shingles vaccine, for example, which is recommended for all healthy adults older than 50, requires a first shot and a booster two to six months later to ensure it is 90 percent effective at preventing the infection and its side effects.

The Pfizer-BioNTech and Moderna COVID-19 vaccines, which are mRNA vaccines, include an initial dose and a second shot three or four weeks later, respectively. Currently, the third COVID-19 vaccine authorized for emergency use in the United States, made by Johnson & Johnson, is given in a single dose, but the company is testing the efficacy of a second booster shot, too. (The U.S. has temporarily paused its distribution of Johnson & Johnson’s current dose, however, as it investigates reports of rare but severe blood clots.) In February, Pfizer-BioNTech launched a study of a third dose of its now two-dose regimen. And yesterday, Pfizer CEO Albert Bourla told CNBC that people would “likely” need a third shot, 12 months after the initial dose.

Each of these vaccines offer impressive efficacy against COVID-19 in their recommended doses. The question that remains, however, is how long that immunity will last—and whether additional shots will be needed in the near (or not-so-near) future to maintain that high level of protection.

The COVID-19 vaccines are brand-new, which means scientists don’t know yet how long they will remain effective without additional intervention. Researchers have monitored the effectiveness of the vaccines in inoculated people, and studies show that they remain highly effective for at least six months.

“Unfortunately, many people have misunderstood that to mean that it lasts only six months,” says Bailey, when, “all that information means is that we know that it lasts six months, and we expect it to last longer.” To know exactly how long protection endures, “we just have to wait and see.”

But, “it’s not obvious that every type of vaccination requires a booster,” says Amesh Adalja, an infectious disease physician and senior scholar at the Johns Hopkins University Center for Health Security. For example, the yellow fever vaccine offers lifelong protection after a single shot. And while the tetanus vaccine has long required a booster shot every 10 years to maintain its effectiveness, researchers have recently questioned whether additional doses are necessary.

What’s more, a vaccine booster is different from what some scientists are testing now: new shots targeted at specific variants.

There are at least five known “variants of concern” of the original SARS-CoV-2, the virus that causes COVID-19; B.1.1.7, which was first identified in the United Kingdom; B.1.351, first discovered in South Africa; P.1, which arose in Brazil; and both B.1.427 and B.1.429, which were first seen in California. Moderna has tweaked its vaccine and is currently testing whether it is efficacious against B.1.351—and a spokesperson for Pfizer told National Geographic that the company is discussing the potential for additional trials of vaccines that would target the variants currently circulating.

So far, the existing vaccines have proven to provide protection against these variants. “I don’t think we’re at that point where you pull a trigger, that you have to change something because of the variants,” Adalja says. But not every infectious disease expert agrees with that assessment.

The new normal

Daniel Lucey, an infectious-disease specialist with Georgetown University Medical Center, says that additional shots to boost immunity or target current or future variants “will most likely be a new reality” for some people. The virus will try to mutate “for its own survival benefit,” he says, and could escape the protection of current vaccines.

Lucey adds, “It’s a constant series of battles and multi-year war between SARS-CoV-2, its variants, and our vaccines, which are from 2019. We’re behind. The virus doesn’t sleep, but we do.”

Matthew B. Frieman, an associate professor of microbiology and immunology at the University of Maryland School of Medicine who has worked with Novavax to develop its yet-to-be released COVID-19 vaccine, agrees. “It’s highly likely” that booster or brand-new shots will be “required in the future” to fight against SARS-CoV-2 variants, Frieman says. “How frequently we need them — and if they’re needed worldwide or in specific populations — is what we don’t know.”

Pfizer-BioNTech and Moderna’s mRNA vaccines are efficacious against the B.1.1.7 variant, which originated in the U.K. but is now the dominant strain in the U. S. But one initial study shows that B.1.351, the variant from South Africa, can break through at least the Pfizer-BioNTech vaccine. However, that study has not been peer reviewed—meaning that it has not yet been examined by a panel of experts—and included only a small sample size of people infected with the variant.

Earlier this month, Pfizer and BioNTech updated their COVID-19 vaccine’s efficacy, saying in an April 1 press release that it was 91 percent efficacious overall and “100 percent effective in preventing COVID-19 cases in South Africa, where the B.1.351 lineage is prevalent.”

Adalja says that if the vaccines dipped to 50 percent efficacy, then a booster or new shot might be needed. The U.S. Food & Drug Administration has said that it expects any COVID-19 vaccine to prevent disease or decrease severity in at least 50 percent of vaccinated people. When considering additional shots, “I think that is a good threshold to keep in mind,” Adalja says.

And if enough people get vaccinated not just in the U.S. but abroad, “you can block the spread of these variants,” says Frieman, which could impact the need for future shots. However, if boosters or new shots are needed, the same is true: people will need to take them en masse to be effective.

The ethical issues of boosters

Teneille Brown, a professor of law and adjunct professor of internal medicine at the University of Utah, says “asking or requiring people to get a booster might be a tougher sell for some,” because it “reflects an ongoing obligation and not a one-time thing.” Take the influenza vaccine, which is recommended for almost all people: only 45 percent of American adults got their annual shots during the 2017-2018 season; 48 percent got them for the 2019-2020 season.

While the U.S. government has not mandated COVID-19 vaccines, vaccine mandates are already taking shape: So-called “vaccine passports” may be required to board airplanes, for example, or to enter foreign countries. Some colleges are requiring on-campus students to be inoculated. And employers can require employees to get COVID-19 vaccines, though it’s unclear how many will.

If additional shots are needed, it’s conceivable that they could also be mandated in these same or similar ways. The burden of vaccine proof raises some ethics concerns, says Faith E. Fletcher, a public health ethicist in the Center for Medical Ethics and Health Policy at Baylor College of Medicine, and has the potential to exacerbate existing social and health inequities.

For example, essential workers and Black and Hispanic people have struggled more than their white counterparts to get initial vaccinations. Without finding ways to “make vaccines available and accessible to marginalized populations,” Fletcher says, “we’re going to see disparities down the line related to this issue,” including with any future COVID-19 shots, mandated or otherwise.

Brown and Fletcher agree that the cost of future doses should be covered. “There would need to be some requirement that the booster shots are covered by insurance, waiving copays, or they will not be equitably distributed,” Brown says, “and we will see gross inequities of who’s getting the booster and who’s not.” Even a $20 copay, she says, could keep people from getting a shot.

But for those who simply don’t want to follow work or private sector mandates for any future shots, “the law is not on their side,” Brown says. Existing laws permit mandates so long as exemptions are available for religious and medical reasons — for example, having an allergy.

Even so, Brown likens such mandates to driving a car.

“If you want to drive, you have to get a license, insurance, etc.,” Brown says. “It isn’t a one-time thing. The privilege of driving creates ongoing obligations to get your car registered, to get your emissions tested, and to continue to comply with changing traffic laws. You might disagree with these laws … but that doesn’t give you permission to ignore them at your choosing.”

Brown says that she is hopeful that any maintenance to keep COVID-19 at bay will become as routine as renewing a license or registration. “I actually think that the ongoing nature will help,” she says, because “resistance will fade with time and [as] vaccines become less politicized.”

This week saw a downturn in the U.S.’s COVID-19 cases, hospitalizations, and deaths, which public health officials attribute to the spread of vaccination across the country. Nationally, the seven-day average of new COVID-19 cases has declined to 54,400, a 21-percent drop from last week. In addition, the seven-day averages for daily hospital admissions and deaths are down from last week’s numbers by 9.1 percent and 5.6 percent, respectively. “Each day, more and more Americans are rolling up their sleeves and getting vaccinated, and likely contributing to these very positive trends,” said Rochelle Walensky, director of the U.S. Centers for Disease Control and Prevention, in an April 27 press conference.

Note: Counties recording fewer than five days of confirmed cases and having fewer than 10 cases are not shown.

As of April 30, the U.S. has administered more than 235 million shots. More than half of U.S. adults now have received at least one dose of a COVID-19 vaccine. Some 38.4 percent of U.S. adults have been fully vaccinated—including over two thirds of those above the age of 65. Over the past week, however, the U.S. has seen a slight decline in the rate of vaccinations, with a seven-day average of 2.7 million jabs per day, down from a mid-April daily high of 3.3 million.

As more of the populace gets vaccinated, the CDC has continued to adjust its guidance for what activities come with a lower risk of getting or spreading COVID-19. The CDC’s updated guidelines, released Tuesday, say that vaccinated people can take off their masks in small outdoor gatherings, or when dining outside with a mix of vaccinated and unvaccinated. The CDC recommends continued masking for large, high-density outdoor events such as concerts and sports games to lessen the risk for unvaccinated people in attendance.

Why vaccine side effects really happen, and when you should worry

(Update 5/30/2021)

Chills, headache, and fatigue after a shot are perfectly normal. But reactions can vary wildly, and they don’t reflect how your immune system would respond to a COVID-19 infection.

Side effects can be a powerful deterrent stopping people from getting vaccinated. To address this issue, in 1991, a group of scientists in Minnesota—at the Department of Veterans Affairs and the Mayo Clinic—devised an experiment to see just how frequent these unpleasant reactions were.

The study involved more than 300 veterans over the age of 65 who were given either a flu shot followed two weeks later by a placebo injection of salt water, or a placebo shot followed two weeks later by the real vaccine.

When the researchers unblinded the study to see who received the vaccine versus the placebo, the side effects were split equally between the two groups, says Robert Jacobson, medical director for the population health science program at the Mayo Clinic. “About five percent said they got sicker than they ever had been in their entire life,” says Jacobson. Half of these people had received the placebo and yet they complained of the worst headaches, or worst fever, of their lives. The take-home message here, says Jacobson: “It’s easy to confuse an allergic reaction with nervousness or emotions or even stomach upsets from anxiety.”

Recent studies show some side effects, even ones from the COVID-19 vaccines, aren’t due to the shots at all, but to our own fears. “We’ve seen this in the military, when young recruits, who think they can tolerate anything, faint when they get the injections, because their body overreacts,” says Jacobson.

It’s a lesson that may be useful to medical professionals, who can reassure patients that most side effects are normal and predictable—and may not even be caused by the shot. Case in point, in studies of the Pfizer/BioNTech vaccine, 23 percent of people aged 16 to 55 who received the placebo complained of fatigue after their second jab, and 24 percent noted headaches.

Studies do suggest that up to seven out of ten people getting their second shot have some type of reaction. Some feel a soreness at the injection site on their arm. They may experience itching or hives, or a range of flu-like symptoms, such as chills and fever, headaches, or debilitating fatigue, that can leave them bedridden for a day or two. Still, it’s important to put these side effects in perspective, says Jacobson, “because these are mild, temporary, and transient reactions that disappear within a few days.”

What causes the immune reactions?

In the case of the authorized COVID-19 vaccines—Pfizer, Moderna, and Johnson & Johnson—all contain a genetic blueprint for manufacturing spike proteins, which sit on the surface of the coronavirus and enable it to infect human cells. When human cells receive these instructions, they churn out copies of spike protein. But since the cells make only a piece of the virus, and not the whole pathogen itself, we don’t get sick. But while the foreign spike can’t cause disease, it can activate a two-step immune response—exactly as it is supposed to do.

The immediate physical reaction to the COVID-19 vaccine is caused by the innate immune system. When a person receives a shot, a flurry of white blood cells called macrophages and neutrophils arrive at the injection site and begin producing chemicals called cytokines. This response triggers a wide range of symptoms, from inflammation and swelling at the injection site to fever, fatigue, and chills.

As a result, side effects are a natural reaction to vaccination. This response—called “reactogenicity”—means the vaccines instigate a strong, initial immune response and trigger a wide range of symptoms. Out of about 3,600,000 vaccinated people who participated in a survey in February, approximately 70 percent reported pain at the injection site, 33 percent felt fatigued, 29 percent suffered headache, 22 percent had muscle pain, and 11 percent experienced chills and fever after their first shot of a COVID-19 vaccine. The symptoms were even more pronounced after the second dose. Still, the innate immune response is short-lived, lasting only a few days.

Why do reactions to vaccines differ and what do they tell us?

But not everyone experiences side effects after a COVID-19 vaccine. Some feel fine after both doses. Scientists don’t really know why, says Sujan Shresta, an immunologist at the Center for Infectious Disease and Vaccine Research at the La Jolla Institute for Immunology, in California. “But it’s not a surprise that each person mounts the immune response differently.”

Several factors can contribute to this wide variation. Women, for example, typically have stronger immune reactions than men, which may be part of what makes them more prone to suffering from side effects from the shots.

“We all have our own individualized immune system,” says John Wherry, director of the institute for immunology at the University of Pennsylvania, in Philadelphia. “It’s almost like our own immune fingerprint that’s driven by genetics, gender, diet, our environment, and even our life history, which are the things our immune system has been exposed to in the past and has been trained to respond to over the years.”

Even if you don’t have an unpleasant reaction, the vaccines are still doing their job, because the real work of the immune system—and of the vaccines—takes place during the second, or adaptive, phase of the immune response. During this phase, the spike protein generated via the vaccine trains the B-cells to produce antibodies that match the virus, and the T-cells to seek-and-destroy infected cells. But it takes days to weeks to provide this long-lasting protection against the virus.

This is also the reason why people often have more rigorous reactions to the second shot. Three weeks after the first shot, the immune system has already been primed, and the B-cells and T-cells are ready to fight. When the second shot is delivered, both the innate and adaptive systems respond.

Still, we don’t really know if having a serious response to the vaccines is a measure of the strength of the immune system. We also don’t know if it means that someone who doesn’t have a strong innate response will be more vulnerable to COVID or more resistant. “We really don’t have any data in the field on this—whether a person with strong side effects would have a more severe COVID infection and vice versa,” says Wherry.

Women experience more side effects

In a February study that looked at the data from the first 13.7 million COVID-19 vaccine recipients, the Centers for Disease Control and Prevention found that nearly 80 percent of the people reporting reactions were female, even though only 61.2 percent of the injections had been given to women. In a similar vein, the CDC reported that all anaphylactic reactions to the Moderna shot have been in women; 44 of the 47 people who’ve had these reactions to the Pfizer injection were female.

The majority of people who have experienced the severe blood clotting issues with the J & J vaccine, and also the AstraZeneca vaccine in Europe and the United Kingdom, have been women. “There has been speculation about hormones playing a role—which is always the first culprit that’s looked at when you see a major sex difference,” says Penn’s Wherry.

Several other factors may also contribute to this gender imbalance. Women also seem to have a more robust immune system, both in their innate responses and in their adaptive immune reactions. “Females mount a stronger antibody response than males but it’s a double-edged sword because this is why women have more auto immune disease than men,” says Shresta of the La Jolla Institute for Immunology.

Other studies have shown that a woman’s response to half a dose of the influenza vaccine was the same as men’s full dose, so females might not need full doses of the COVID-19 vaccines. “We have this idea that one size fits all, but this may be part of what’s contributing to the higher rate of reactions among women,” says Rosemary Morgan, a scientist specializing in gender research at the Johns Hopkins Bloomberg School of Public Health. “There is also a behavioral component—women are more likely to visit the doctor and to be more proactive about reporting unpleasant symptoms.”

Side effects versus adverse events

“But side effects and adverse events—which often get conflated—are not the same,” says Wherry. “Side effects are pretty common—occurring maybe 50 to 70 percent of the time. But adverse events are rare and unexpected, like the clotting disorders.”

Immediately after injection, about two to five people per million experience anaphylaxis, a severe allergic reaction that causes a dramatic drop in blood pressure and difficulty breathing. But even this is easily treatable with an EpiPen and antihistamines, which is why everyone is asked to stick around for 15 minutes after their COVID-19 shots.

The blood clots associated with the Johnson & Johnson vaccines, that have occurred within six to 13 days of receiving the shot, can be dangerous and even life threatening. But the incidence is quite low; there are only 23 confirmed cases out of 8.4 million doses of the vaccine.

“This is very rare,” says Ofer Levy, director of the precision vaccines program at Boston Children’s Hospital and a professor of pediatrics at Harvard Medical School. “The risk of getting COVID and possibly dying is much higher than getting blood clots from the vaccines.”

Are we noting all the adverse effects?

There is some worry that there may be other adverse effects that have gone largely unreported.

The three COVID-19 vaccines that have been authorized in the United States have been tested on tens of thousands of people in clinical trials, and manufacturers were required to follow up with at least half the vaccine recipients for two months or more after they received both shots. But now that more than 116 million Americans have been fully vaccinated, rare side effects that don’t show up in smaller human clinical trials can emerge—which is why surveillance systems are important.

Here in the U.S., we have a patchwork of systems: the Vaccine Adverse Event Reporting System (VAERS), the Vaccine Safety Datalink, and the CDC’s new phone-based tracking program, v-safe.

All of these have limitations, including that “someone has to suspect these health outcomes are related to vaccination and go to the trouble of filling out the form,” says Katherine Yih, a biologist and epidemiologist at Harvard Medical School, specializing in infectious diseases, immunization, and vaccine safety monitoring. “We have a vigorous surveillance system in place. But we can’t be sure it’s picking up everything.”

What’s more, these incidents only show correlation. In other words, if someone died or had a stroke after getting vaccinated, physicians don’t know if it was triggered by the shot. Only further study can reveal that.

The swift identification of the rare blood clotting disorder related to the J & J vaccine was reassuring. Initially, six cases were reported, prompting the FDA and the CDC to temporarily halt its use. When the CDC’s Advisory Committee on Immunization Practices met in late April to determine the vaccine’s fate, 15 cases had been detected out of seven million people who had the shot. “The discovery of that association with the J & J vaccine—which is very rare—is a real demonstration of how good our safety program is,” says the Mayo Clinic’s Jacobson.” At this point in the pandemic, a risk of less than three per million should not enter into our calculus of how to proceed.”

A spritz instead of a jab? Future COVID-19 vaccines may go up your nose.

Spurred by the pandemic, scientists are studying the benefits of intranasal vaccines and what makes them more potent than shots in the arm.

(Updated 7/25/2021)

The current batch of COVID-19 vaccines effectively prevents severe disease and death and offers substantial protection against the variants. But the authorized vaccines are not 100 percent effective at blocking all infections. To address this deficit, scientists are exploring new ways of delivering vaccines that yield stronger and more durable immunity against SARS-CoV-2. One promising approach might be to trade a jab in the arm for a spritz up the nose.

Over the past several months, as some manufacturers are preparing booster shots to deliver a third dose, a handful of promising studies have revealed the effectiveness of intranasal vaccines in mice, ferrets, hamsters, and non-human primates. Further along are six candidate COVID-19 vaccines, administered as nasal sprays, that are currently in phase 1 clinical trials. And, just this week, at the meeting of the American Society for Virology, Meissa Vaccines announced that a single dose of their intranasal COVID-19 vaccine candidate showed promising results in non-human primates. If these vaccines come to market, immunologists say that might offer better protection because they more closely resemble the way the virus naturally infects us—through the mucous membranes of the nose and upper airways. And immunologists say this makes a difference in the immune response.

“If you want to generate a sustainable, long-lasting immune response, you want to vaccinate locally,” says José Ordovas-Montañes, a Harvard University immunologist who studies immunity in the gut and nasal mucosal tissues. Ordovas-Montañes says that when we get a jab in the arm, we are inducing immunity on a systemic, body-wide scale where our antibodies and T cells will distribute themselves around the blood vessels. While that might sound good, this approach is “sub-optimal” because the immune cells are “distracted” and not focused on the location where the virus enters the body. A shot up the nose, on the other hand, provides a big boost of immunity in the upper respiratory tract and potentially the lungs, eliciting a local antibody response and T cell response. This enables immune cells to apprehend and destroy the pathogen on arrival.

“I think the big benefit is that you generate immunity at the site of infection,” says Donna Farber, an immunologist at Colombia University. “That’s where you need the immunity, where the virus is coming in.”

A shot in the arm is like vaccinating us from the inside out. We generate immunity throughout the body, and some of those antibodies trickle into the airways and nasal passages. But the nasal spray works the other way around, boosting the site of infection first and the rest of the body second. “You basically get a two for one,” says Paul McCray, a pediatric pulmonologist at the University of Iowa.

McCray and colleagues published a paper this month in Science Advances showing that mice and ferrets are protected from severe diseases after just one dose of an intranasal vaccine. They will be launching a clinical trial later this month for 80 healthy adults ages 18 to 75 years at three sites around the U.S.

A more practical vaccine

Vaccines that target the mucous membranes aren’t new. There are many oral vaccines that are approved to combat infections such as polio and cholera. The idea is that they will prime the mucosal tissues of the intestinal tract in much the same way as intranasal vaccines prime the respiratory tract. In many cases, like in the live attenuated oral polio vaccine, these vaccines work better than the shot. But intranasal vaccines remain rare in the vaccine landscape overall. Many are hoping that the pandemic will change that.

“COVID has really accelerated the development of some things that were always right in front of us hiding in plain sight,” says David Curiel, a gene therapy researcher at Washington University in St. Louis. Earlier this year, he published a study showing a robust response after a dose of an intranasal vaccine in non-human primates. He points out that another benefit to developing these kinds of vaccines is that they could be easier to administer, especially around the world in places that do not have well-established healthcare systems. 

The current batch of approved vaccines are highly efficacious, but there aren’t enough doses to vaccinate everyone in the world, and the pandemic is far from over, especially in India and several countries throughout Africa and South America. Forgoing the needle, something that could be in short supply, would be advantageous. The COVID-19 vaccines may mark a new era in mucosal immunity.

Where does our immunity live?

When the immune system is discussed, most people think about blood. Immune cells are often described as mini watchers that patrol the blood vessels looking for invaders. But, over the past decade or more, understanding of the immune system has evolved and researchers now know that many immune cells reside in the tissues.

More than 95 percent of T cells, for example, take up permanent residence in the tissues and organs, with distinct populations dwelling in the skin, gut, brain, liver, and lung. Natural killer cells, which are related to B and T cells, spend their lives in the uterus remodeling the tissue during pregnancy. There are even some immune cells, called microglia, that live in the brain and never journey into the blood vessels. Instead, they migrate to the central nervous system early in embryogenesis and stay there for the remainder of the organism’s life.

These tissue-specific immune cells can work to our advantage when it comes to vaccines because they not only remember the pathogen but also where it first invaded the body.

The immune system has developed an elegant way of doing this called “immune imprinting,” says Ulrich von Andrian, an immunology professor at Harvard. Von Andrian was the first to demonstrate, in mice, how the immune system keeps track of where a particular pathogen entered the body.

The immune system is alerted to new threats when specialized cells, called “antigen-presenting cells,” such as macrophages, pick up little bits and pieces of the virus around the body and present them to the T cells. This process is called “T cell education,” and it is the immune system’s version of an intelligence briefing. It takes place in the lymph nodes, where all the lymph fluids drain, along with the cells and bits of viruses. These little training centers are located throughout the body, and as anyone who has gotten very sick and experienced a swollen lymph node can attest, they are particularly abundant in the neck, armpit, and the groin. Von Andrian showed in his seminal experiment that the intelligence briefing not only contains info about the specific threat, but also the location where it was first spotted.

In an experiment from his lab back in 2003, T cells were removed from mice and put into different petri dishes, where they were mixed with antigen-presenting cells from lymph nodes, skin, and the gut. After about a week in the petri dish, the T cells were injected back into the mice. The T cells that were educated with antigen-presenting cells from the gut, immediately swarmed back into the gut. Like a homing pigeon that flies great distances to get back home, these cells had an innate sense of where to go. They remained there for a long time, standing guard for an invasion.

Von Andrian says that the lymph nodes teach the T-cells how to migrate back to the part of the body where they first encountered the pathogen. The lymph nodes closest to the nasal tissues reside in the neck; and the lymph nodes connected to the arm, where vaccine shots are administered, are “in a different part of town.”

“When you get an infection, you get it in your mucosal surfaces in your nasal cavity, and you prime your T cells and your entire immune system in your upper respiratory tract, which means these cells are going to stay there, become resident, and act like a sentinel defense,” says Marcus Buggert, an immunologist and T cell researcher at the Karolinska Institute in Sweden. “If you vaccinate yourself in the arm, you won’t induce that type of T cell response.”

Coronavirus in the U.S.: Where cases are growing and declining

(Update 5/3/2021)

New cases, hospitalizations, and deaths are on the decline this week, which experts attribute the national rise in vaccinations.

This week saw a downturn in the U.S.’s COVID-19 cases, hospitalizations, and deaths, which public health officials attribute to the spread of vaccination across the country. Nationally, the seven-day average of new COVID-19 cases has declined to 54,400, a 21-percent drop from last week. In addition, the seven-day averages for daily hospital admissions and deaths are down from last week’s numbers by 9.1 percent and 5.6 percent, respectively. “Each day, more and more Americans are rolling up their sleeves and getting vaccinated, and likely contributing to these very positive trends,” said Rochelle Walensky, director of the U.S. Centers for Disease Control and Prevention, in an April 27 press conference.

As of April 30, the U.S. has administered more than 235 million shots. More than half of U.S. adults now have received at least one dose of a COVID-19 vaccine. Some 38.4 percent of U.S. adults have been fully vaccinated—including over two thirds of those above the age of 65. Over the past week, however, the U.S. has seen a slight decline in the rate of vaccinations, with a seven-day average of 2.7 million jabs per day, down from a mid-April daily high of 3.3 million.

As more of the populace gets vaccinated, the CDC has continued to adjust its guidance for what activities come with a lower risk of getting or spreading COVID-19. The CDC’s updated guidelines, released Tuesday, say that vaccinated people can take off their masks in small outdoor gatherings, or when dining outside with a mix of vaccinated and unvaccinated. The CDC recommends continued masking for large, high-density outdoor events such as concerts and sports games to lessen the risk for unvaccinated people in attendance.

Where can you travel safely once you’ve had the COVID-19 vaccine?

(Updated 3/19/2021)

After more than a year of COVID-19 pandemic restrictions, the U.S. Centers for Disease Control and Prevention (CDC) released an official statement many of us have been longing to hear: vaccinated people can safely engage in many activities

At press time, 11 percent of the United States population had been fully vaccinated against COVID-19, and 21 percent had received at least one dose. For the inoculated, the news is good—but the temptation to take a trip is greater.

Last Friday, some 1.357 million people passed through U.S. airports, according to the Transportation Security Administration. It was the highest single-day tally since the World Health Organization declared the coronavirus outbreak a pandemic in March 2020. Such activity is possibly at odds with the latest CDC guidelines, which stipulate that even fully vaccinated people should avoid travel unless necessary.

As travel rules start lifting, here’s what vaccinated visitors need to know before planning an international trip.

Vaccines protect you more than others

Travel will become safer for those who have been inoculated and have built up COVID-19 antibodies. “As a vaccinated traveler, you are almost 100 percent protected from severe disease if exposed to SARS-CoV-2,” says Monica Gandhi, an infectious disease doctor and professor of medicine at the University of California San Francisco.

Early studies show that vaccines are preventing viral transmission too, meaning vaccinated people are unlikely to spread COVID-19. But until that’s confirmed—results of several clinical trials are expected by fall—you’ll need to maintain the usual virus-transmitting precautions.

(After you get a COVID-19 vaccine, here’s what you can do safely)

Other unknowns—how long immunity lasts after vaccination, what will happen with those dangerous variants—will continue to vex scientists and challenge populations.

Once vaccinated, the main worry for a traveler is giving COVID-19 to other people while in transit to or at a destination. “It is still important to practice precautions known to mitigate risk to you and to others: wear a mask, keep your distance, wash your hands, [choose] outdoors over indoors, and avoid crowded spaces,” says Joyce Sanchez, infectious disease doctor and medical director of the Travel Health Clinic at Froedtert and the Medical College of Wisconsin.

Where can you go?

Government travel advisories and border rules will continue to dictate choices. Research your options via the U.S. Department of State’s country pages, the CDC’s recommendations by destination, or, which tracks countries by vaccination rate, entry rules, and lockdown status.

Testing is essential. Not only is proof of a negative COVID-19 test required by many international destinations, it is also required for U.S. citizens flying home from abroad. As of January 12, Americans must be tested no more than three days before flying back from outside of the country and show a negative result to the airline before boarding (or present documentation of recovery from COVID-19). You can research testing rules for other countries via

Dozens of countries are open to U.S. travelers, with an ever-shifting patchwork of requirements and regulations to visit. Some (United KingdomPeru) require both negative COVID tests and quarantines; others, such as Mexico and Costa Rica, have few restrictions beyond temperature screenings.

Many Caribbean destinations—including JamaicaSt. Kitts and Nevis, and Dominica—will permit U.S. travelers with a negative result from a lab-issued COVID-19 PCR test that’s no more than 72 hours old upon arrival. The Dominican Republic no longer requires U.S. visitors to show a negative COVID-19 PCR test result on arrival.

In what may be the new normal for “vaccination vacations” to come, Seychelles is now open only to travelers—Americans included—who have been fully inoculated and can show proof.

Vaccine passports are in the works for citizens of countries including Iceland, Poland, and Portugal, as are electronic travel passes from organizations like the World Economic Forum and the International Air Transport Assocition. The CDC hasn’t yet implemented such a program, which could be riddled with practical and ethical issues. Certification indicating you are vaccinated would be easy to forge, and creating a group of vaccinated people who can travel while others can’t seems elitist.

Another good choice is Rwanda, where one of the world’s swiftest COVID responses successfully protected both its citizens and its endangered mountain gorillas. This allowed the east African nation to reopen to tourism in August 2020.

Countries that managed the pandemic well are likely to continue doing so, making tourism in these places safer for everyone as borders open up. Finland, for example, has fewer than 70,000 COVID cases, the Koronavilkku contact-tracing app, and its FINENTRY program provides free testing for travelers upon arrival.

Still, there’s a catch: Places with strict COVID-19 protocols and low caseloads (New ZealandTaiwan) may be slow to let Americans back in—and quick to reimpose rigorous preventative measures, meaning, says Sanchez, “you may run the risk of being stuck in a new lockdown if cases rise during your stay.”

Traveling responsibly

Because mass vaccination efforts are currently underway, the destinations and activities you choose as a traveler can play an important role in shielding yet-to-be-vaccinated locals.

Once border rules allow Americans to visit, inadvertent virus spread will cause less damage in countries with the highest vaccination rates (these include IsraelSeychelles, and the Maldives) than in countries with weaker vaccination programs and less robust healthcare infrastructures.

In Singapore, almost all frontline transportation workers have their first dose. In Bali, Indonesia, tourism workers have vaccination priority. In Thailand, which managed the pandemic well, efforts to accelerate vaccinating residents of popular resort island Phuket aim to allow vaccinated travelers to visit quarantine-free by October.

As rules start to relax, vacations that minimize public transportation and crowds are your best choices. Save festivals and nightclubs for later; now’s the time for exploring outdoors, planning a road trip to Canada’s British Columbia, or exploring Malta’s walkable cities.

All-inclusive resorts have always aimed for worry-free vacations, so many of them have been quick to implement robust COVID protocols that benefit guests andemployees. Even better are naturally isolated destinations and experiences, including parklands, private islands, and safari conservations.

How can you help protect locals?

Most travelers want to know they’re helping, not hurting, a destination’s population. Until everyone has access to vaccines, travelers need to balance how to support tourism-reliant economies while not putting their residents and healthcare systems at risk.

The pandemic increased the already-wide gap between marginalized people and those who have the privilege to travel. But, according to some experts, it’s important not to avoid destinations with COVID-jeopardized economies until their populations are vaccinated.

“The ethical economic considerations are about not isolating areas because of their inability to get the vaccine on time,” says Judy Kepher Gona, founder of Sustainable Travel & Tourism Agenda which works to catalyze sustainable tourism in Africa.

“For some developing countries, the risk of disease infection is more acceptable than the risk of industry failure and significant economic decline,” says Greg Klassen, partner at Twenty31 Consulting, which helps tourism destinations prepare for the future. He says it’s not up to citizens in developed countries to decide for those in developing countries.

In short, embrace companies that prioritize the health and safety of staff and their communities. And choose destinations that have made strong efforts to protect locals and sustain robust healthcare systems. Responsible research and planning will do far more good for everyone than free hand sanitizer.

Are we there yet? What happens if the U.S. can’t reach herd immunity.

(Update 6/4/2021)

Without herd immunity, the country will see localized surges. But even if we don’t get there, experts say there’s still reason for hope.

Herd immunity is often seen as the end game of the COVID-19 pandemic. This threshold is reached when the virus cannot easily spread because most people have built up immunity through vaccination or natural infection. Then, “the virus just can’t find anyone to infect,” says Monica Gandhi, a professor of medicine and infectious diseases expert at the University of California, San Francisco, and the threat fades.

Experts estimate that we’ll reach herd immunity for COVID-19 when 65 to 80 percent of the population is vaccinated—a number that seemed within reach in the U.S. once highly effective vaccines started being administered. But after peaking at a seven-day average of more than three million doses in early April, the rate declined, and the country is now administering an average of a million doses a day.

Amid a swirl of misinformation, distribution issues, and legitimate hesitancy, as of June 3, only 51 percent of Americans have received at least one shot, and just 41 percent are fully vaccinated.

On June 1, U.S. President Joe Biden announced that anyone in America can get a free round of beer from Anheuser-Busch if they get vaccinated. It’s one of the latest government incentives being offered to help meet his administration’s goal of getting 70 percent of adults at least partially vaccinated by July 4, a key milestone in the nation’s bid to reach herd immunity. Some states are also offering big lottery winningsfree iced coffee, or—in West Virginia—trucks and custom hunting rifles.

Still, other experts say it’s possible the U.S. will never reach herd immunity. In a recent Kaiser Family Foundation survey, 13 percent of U.S. adults said they will “definitely not” get a vaccine. So what happens then? Here’s what scientists have to say about where the U.S. stands now, what that means for the return to life as we once knew it, and why there’s still cause for hope even if we can’t hit the target number for herd immunity.

What is herd immunity?

The concept of herd immunity is fairly simple: Picture a herd of cattle. If one animal in the herd gets infected by a virus and none of the rest are immune, then the virus can spread throughout the whole group, potentially sickening or killing each animal. But if some cows gain immunity, they can block transmission to their neighbors.

Calculating how many people within a population need to develop immunity to protect the rest of the herd depends on a few factors: how quickly a pathogen can spread from person to person; how susceptible the population is to infection; and individual behaviors that can either promote or mitigate transmission, such as whether people adopt masking and social distancing.

Herd immunity occurs when an infected person spreads the virus to an average of less than one other person. In the earliest stages of the pandemic, the average for SARS-CoV-2 transmission was between three and four new cases per infected individual. At that point, scientists believed achieving herd immunity would require 60 to 70 percent of the population to be vaccinated.

But as more virulent variants have emerged that spread more easily, that threshold has risen to 65 to 80 percent, says Saad Omer, an infectious disease epidemiologist and director of the Yale Institute for Global Health. In December, White House advisor Anthony Fauci even suggested herd immunity might require vaccinating up to 90 percent of the population.

But herd immunity is not the same thing as eradication—a fact that experts say has often been misunderstood during the pandemic. Crucially, while herd immunity slows transmission, outbreaks can continue even after a society reaches that threshold, says Michael Osterholm, director of the Center for Infectious Disease Research and Policy at the University of Minnesota.

Think of the measles or diphtheria: Even though the general public doesn’t have to worry about them, local outbreaks still occur. As with seasonal influenza, diseases can also become endemic, circulating in a population at a less virulent level but capable of breaking through when our defenses slip. (Here’s why COVID-19 will likely be with us forever.)

“What herd immunity thresholds get you is more sustainable, more long-term control of the outbreak,” says Omer.

What happens if we don’t reach herd immunity?

Some experts worry, however, that this threshold is slipping out of reach. Even with the authorization of Pfizer’s vaccine for emergency use in adolescents, the New York Times estimates that the country won’t get first doses into 70 percent of its population until October—and that’s only if the vaccination rate doesn’t continue to decline. Meanwhile, large pockets of unvaccinated people remain throughout the country, including children under 12, who are not yet eligible.

Osterholm likens the herd immunity threshold to a weather forecaster reporting on a nationwide average temperature rather than local conditions. Vaccination rates—and the protections that come with them—vary from community to community. While most states in the Northeast have given at least one dose to more than 60 percent of their population, a slew of Southern, states including Mississippi and Louisiana, have reached fewer than 40 percent.

“The nature of coronavirus and other infectious diseases is they find where we’re vulnerable,” says Amber D’Souza, professor of epidemiology at the Johns Hopkins Bloomberg School of Public Health. “So wherever the pockets of people are that are not protected, there will be flare-ups in infections. It’s just a question of how long it takes for them to happen.” (The next phase of the U.S. pandemic? Pockets of localized outbreaks.)

Natural infections can help fill in the immunity gap, but Omer says it’s impossible to say for sure how much of the population has natural immunity. It’s also unclear how long natural immunity lasts and to what extent; however, Osterholm says it’s clear that the vaccines offer superior immunity.

If the U.S. doesn’t reach herd immunity, there will be more outbreaks than if the country did cross the threshold. But the situation likely won’t be as dire as it was in January, when hospitalizations and deaths peaked across the nation. Instead, Omer says, there would be periodic smaller surges and loss of life as people head back indoors in the fall and winter.

“That does not mean that we will have to shut down the whole country every time that happens,” Omer says. “But remember if there’s a flood in one month and it’s up to your neck in another month, it’s still pretty bad even if it’s not above your head.”

Osterholm also cautions against a false sense of security in communities with low levels of vaccination—including Southern states—even if their case rates are falling right now. “Why the virus does what it does, why does it come and go, we don’t know,” he says. “We have to be careful not to interpret the absence of cases right now as meaning that we’re protected.”

D’Souza adds that infectious diseases are dynamic: As long as the virus is allowed to circulate anywhere—both in pockets of the U.S. and in countries that don’t yet have wide access to vaccines—it poses a threat to the immunocompromised and others who can’t get vaccines. It also has the potential to give rise to variants that evade the vaccines.

And there’s still much that’s unknown about how long the vaccines protect against the virus and whether booster shots will be needed. Even if the U.S. reaches herd immunity, it could easily be lost.

“One of the challenges we’re going to have with herd immunity is that it’s also not a static situation,” Osterholm says. “Vaccinated today doesn’t mean necessarily vaccinated next year.”

Why there’s reason for hope

But scientists stress that it’s not all doom and gloom.

“I’m concerned about the slowing pace [of vaccinations], but on the other hand there are signs of hope as well,” Omer says, citing the country’s falling rates of cases, hospitalizations, and deaths. “I think that we are seeing the indirect effects of the vaccines kick in.”

Just as herd immunity does not mean a virus has been eradicated, it also is not a hard line that you have to cross to receive any benefits from vaccination. D’Souza argues that herd immunity should be thought of as a gradient rather than a single number: As more people get vaccinated, the entire population is better protected.

“We may never get to 80 percent vaccination, and that could be okay,” she says.

Omer points to the impressive rates of immunization among people who are more vulnerable to death and severe disease. According to the CDC, 75 percent of people age 65 and older are fully vaccinated and nearly 86 percent have received at least one dose. Omer, who was on a committee advising the CDC on how to prioritize vaccination, says this was intentional.

“We all want to see infection rates go down, but we want to see the deaths go down first and more sharply,” he says. Indeed, those numbers have been falling. Nationwide deaths are down from an average of more than 3,500 per day to about 500. New cases have fallen, too, to a seven-day average of fewer than 15,000. “That has given us room to do a lot more stuff socially and physically.”

Gandhi points out that since behavioral restrictions are one way of controlling an epidemic, you need to ease controls somewhat to know whether you’ve actually achieved herd immunity. Some good news on that front comes from Israel, where the country’s case rate had dropped so low by April 19—when just 54 percent of the population had received two doses—that it prompted the government to ease restrictions.

“It was pretty fascinating because as they’ve done that gradual opening, there were no increases in cases,” Gandhi says.

Osterholm says that, while he doesn’t believe true herd immunity is in the cards in the U.S., that doesn’t diminish the importance of getting more people vaccinated. Vaccinating 50 to 70 percent of the population with a vaccine that’s 95 percent effective at preventing COVID-19 will go a long way.

“It’s going to be harder for the virus to find anybody,” he says. “It’ll still find them, but it’ll be slower. And the closer we get to having more people vaccinated, the more protected unvaccinated people will be.”

In the U.S., D’Souza says the coming weeks and months will be critical to see if state vaccination rollouts sputter out, or if children are vaccinated at high rates as shots for younger age groups come available.

“The more people we get vaccinated, the higher that benefit will be,” she says. “We want to get back to a place where people can go to a big concert and not worry, where schools can be open when they’re distancing or masking. That’s the goal—to be able to get back to no worrying.”

Top 10 Reasons To Believe the Wuhan Virology Lab Caused 2019-nCoV

+10. The Outbreak Started Across The Street From A Virology Lab

The official story is that 2019-nCoV started in a seafood market in Wuhan. Unclean animals sold there were carrying the virus, Chinese scientists have suggested, and, as a result, some unlucky shoppers ended up becoming patient zeros for a global crisis.

You’ve probably already heard that explanation before, and there’s a good chance you’ve accepted it as a fact — but there are some glaring problems with it.

For one thing, the first patients with 2019-nCoV have no connection to the market whatsoever. They lived nearby, and they appear to have spread the disease to people who went there — but the real patient zeros never actually stepped foot inside of it.[2]

Also, 2019-nCoV is believed to have originated in bats — and this was a seafood market. Nobody was selling bats inside of this market. Bats just aren’t something people in Wuhan normally eat.

Even China’s scientists have started backing away from this theory. To quote one directly:

“It seems clear that [the] seafood market is not the only origin of the virus… But to be honest, we still do not know where the virus came from.”

A lot of people have pointed to the Wuhan Institute of Virology, which is just a 30 minutes drive for the seafood market. But if that’s not close enough for you, there’s another lab that researches bat coronaviruses that’s even closer: The Wuhan Center for Disease Control & Prevention.

It’s not just on the other side of town. It’s on the other side of the street.

+9. The Wuhan Virology Lab Was Studying Bat Coronaviruses

The Wuhan Center for Disease Control & Prevention isn’t just an administrative office. Scientists were inside that building actively conducting research — including studies on coronaviruses in bats.

A lot of researchers in Wuhan were. It had been a major project for the city, and the Wuhan Institute of Virology took great pride in. They were at the forefront in researching the causes of SARS, and it was their researchers who had proven that the last SARS outbreak originated in bats.

They had to look at an awful lot of sick bats to do it, though. Researchers had been gathering bats infected with the coronavirus since at least 2012, and they were focusing on ones that could spread their illness to human beings.

There were hundreds of bats in Wuhan’s labs when the 2019-nCoV outbreak started, and the researchers there were studying at least 11 new strains of SARS-related viruses in them. And, yes — they were doing it across the street from the place where the outbreak started.

+8. 2019-nCoV Is a 96% Match For A Bat Virus In The Wuhan Virology Lab

The coronavirus that’s spreading around the world at this very moment has been called “novel” because it’s unique. It’s different from past diseases, like SARS. About 30% different, to be exact.

That’s not just a number we pulled out of our heads. Scientists have compared the genetic sequence of SARS to 2019-nCoV, and they’ve found that they’re about 70% similar.

That’s a rough number — the real one might be a bit higher. But the real number probably isn’t 96% — which is the percentage match scientists have found between 2019-nCov and a form of the coronavirus carried by bats inside of the Wuhan Institute of Virology.

“But wait a minute,” you say. “If those bats had the virus, there were probably bats all around Wuhan that had it — right?”

Afraid not. 2019-nCoV isn’t just similar to bat coronaviruses in general — it’s similar to a very specific strain of bat coronavirus carried by bats in the Wuhan Institute of Virology. Not every bat coronavirus has that 96% match — in fact, when another lab compared 2019-nCoV to their own bats, the closest match they could find was 88%.

And those bats weren’t local. If you were living in Wuhan and you really wanted to find one of those bats, you’d either have to go to the virology lab or to the place those bats had come from: Yunnan and Zhejiang.

That’s a little over 900km away.

+7. An Infected Bat Bled On A Researcher Shortly Before The Outbreak

Ok, so a disease lab was researching diseases. So what? That doesn’t prove that it ever got out — right?

While it’s highly unlikely that the Wuhan Institute of Virology deliberately plagued its own people, it really wouldn’t have been that hard for somebody to catch it by accident.

Imagine if a bat attacked a researcher and, in the chaos, spilled its blood onto his bare skin. Or imagine if he got a bit too close and got bat urine on his body. Or imagine both of those things happened to the same person not long before the 2019-nCoV outbreak began.

That’s exactly what happened. According to a report by Chinese researchers Botao and Lei Xiao, a researcher named Junhua Tian described these exact experiences in an interview with the Changjiang Times.

Junhua Tian claims he quarantined himself to keep from spreading these disease — but even if he and his colleagues used every possible precaution, it’s possible that the virus still could have leaked out.

One thing we’ve learned since the outbreak is that people can show no symptoms at all and still be infected. And, according to a recent study out of Japan, people who have recovered can still carry the virus.

+6. SARS Escaped From A Beijing Lab Twice

Of course, it’s also possible that the staff at the Wuhan Institute of Virology just didn’t use every possible precaution.

It wouldn’t be the first time someone’s walked out of a Chinese virology lab carrying a deadly sickness. It’s happened before — in fact, it once happened twice in a single month.

On April 4, 2004, a postgraduate student working at a virology lab in Beijing was diagnosed with SARS. She had gotten infected while researching the virus, and, unaware that she was sick, walked out into the public and very nearly caused a second outbreak.

That’s pretty bad — but what makes it downright terrifying is that, two weeks later, another postgraduate student working at the exact same lab did the exact same thing.

That’s not just negligent. According to scientist Antoine Danchin, it should technically be impossible.

“Normally, it’s not possible to contaminate people even under level two confinement if the security rules are obeyed,” he said after the incident. “It suggests there has been some mishandling of something.

“The lab might have all the right rules, but the people may not comply.”

+5. The Wuhan Virology Lab Was Testing A Virus That Matches 2019-nCoV

In case there was any doubt, the Wuhan Institute of Virology definitely had postgraduate students on staff.

We can confirm that because, on Nov. 18, 2019, shortly before the breakout, the institute put up a job posting[17] asking for postgraduate students to help study the coronavirus in humans and bats.

That’s not exactly out of the ordinary — but the description in the job posting is a little disturbing. It says that they were particularly interested in molecular mechanisms that let coronavirus lie dormant for a long time without symptoms.

Sound familiar? That’s one of the distinguishing traits of 2019-nCoV — the fact that people can go around without any apparent symptoms and still spread it.

322 of the people on the Diamond Princess cruise ship tested positive without symptoms, and there’s proof that those asymptomatic people can spread the disease. In fact, one woman is confirmed to have spread it at least five people without showing any symptoms of her own.

+4. Researchers At The Lab Had Recently Created A New Coronavirus

The staff at Wuhan Institute of Virology didn’t just work on cures. They also spent some developing new, super viruses of their own.

In 2015, two researchers at the Institute participated in an international experiment led by American scientist Ralph Baric. The goal? Create a new coronavirus with the ability to infect human beings.

If that sounds like a weird goal to you, you’re not alone. A significant part of the scientific community was outraged by this experiment.

“The only impact of this work is the creation, in a lab, of a new, non-natural risk,” biologist Richard Ebright protested when the work came out.

French virologist Simon Wain-Hobson agreed. “If the virus escaped,” he warned, “nobody could predict the trajectory.”

+3. 2019-nCoV Has Eerie Similarities to HIV

According to a controversial study out of India, some aspects of 2019-nCoV have “uncanny similarities” to HIV.

Full disclosure — this study’s gotten a fair degree of scrutiny. Some scientists have questioned whether it used enough data to be statistically significant, and they’ve put it through the wringer enough that, at this point, the study’s authors have withdrawn their work.

But while their work might be unproven, that doesn’t necessarily make it wrong — and there’s a little bit of evidence to back it up. HIV drugs are proving to be remarkably effective in treating the drug, and most patients are showing low white blood cell counts — something that doesn’t happen with any other form of coronavirus.

That’s creepy — because researchers in the Wuhan Institute of Virology have worked on or conducted studies combining SARS-CoV and an HIV pseudovirus in bats and humans.

There’s no hard proof that the 2019-nCoV is a man-made virus — but if scientists ever find proof that it is, there’s a lot of reason to be worried.

+2. The Communist Chinese Government Ordered Silence

Infectious disease specialist Daniel Lucey got the chance to review the documents and data China had in its possession when 2019-nCoV broke out, and he came out of it baffled. Their official story, he said, just didn’t make any sense.

“China must have realized the epidemic did not originate in that Wuhan Huanan seafood market,” Lucey told the press.

Perhaps he was right. Perhaps somebody in Wuhan knew that the story didn’t add up even when they first announced it. But if they did, they were under strict orders not to say anything about it.

On Jan. 2, 2020 — the day after the Huanan seafood market was blamed for the disease — the Wuhan Institute of Virology sent out a disclosure strictly “prohibiting disclosure of information” on 2019-nCoV.

Some scientists have spoken up anyway. A good part of this article, for example, draws from a study by the National Natural Science Foundation of China called “The possible origins of 2019-nCoV coronavirus”.

It might not surprise you to find out that, shortly after that study was released, the communist government did its best to pull it off the internet with as much vigor as they are using in attempting to stop people referring to the virus as a “Chinese virus” or as the “Wuhan flu”.

+1. The Chinese Government Is Tightening Up Biolab Security

The biggest smoking gun of them all came straight out of the mouth of President Xi Jinping.

On Feb. 14, 2020, President Xi gave a speech on the need to contain 2019-nCoV. Chinese, he said, needs to “learn our lessons… so we can strengthen our areas of weakness and close the loopholes exposed by the epidemic.

While Xi was never completely explicit about how those loopholes were to be closed, he did announce his plan to push through a new law for “biosecurity at laboratories” specifically targeting the use of biological agents that “may harm national security”.

The very next day, the Chinese Ministry of Science and Technology followed up on Xi’s speech with a new directive entitled: “Instructions on strengthening biosecurity management in microbiology labs that handle advanced viruses like the novel coronavirus.”

There’s only one microbiology lab in all of China that handles advanced viruses like the novel coronavirus.

It’s the Wuhan Institute of Virology. (Update 1/5/2021)

Information from The Next Revolution w/Steve Hilton on the Origins of the Coronavirus

We still don’t know the origins of the coronavirus. Here are 4 scenarios.

(Update 4/3/2021)

Experts say that understanding how the virus first leapt from animals to humans is essential to preventing future pandemics.

The search continues for the origins of the virus that causes COVID-19—and the pathway that it took to leap from animals to humans, wreaking havoc across the globe, infecting more than 129 million people, and killing more than 2.8 million.

Earlier this week, the World Health Organization released a report from a team of international researchers that traveled to China to investigate four possible scenarios in which the SARS-CoV-2 virus might have caused the initial outbreak. In the days since, however, world governments have expressed concern that the investigators lacked access to complete data, while scientists say that the report has shed little light on how the virus got jumpstarted.

That’s unsurprising given that it typically takes years to trace a virus back to its roots—if it’s possible at all, says Angela Rasmussen, a virologist at the Center for Global Health Science and Security at Georgetown University Medical Center. But in this case, she says, “I think we do have enough evidence to say that some are more likely than others.”

In the report, the team found that the virus most likely jumped from one animal to another before making its way to humans. They also looked at evidence supporting theories that the virus passed into humans directly from an original host animal, or that it traveled through the supply chain for frozen and refrigerated foods. In addition, the team addressed the possibility that the virus accidentally leaked from a laboratory in Wuhan—a scenario they determined is “extremely unlikely.”

Here’s a look at the evidence the report lays out for each of the four theories—and what experts make of them as possible origin stories for SARS-CoV-2, the virus that causes COVID-19.

1. Direct spillover from animals to humans

WHO ASSESSMENT: possible to likely

The first origin story for SARS-CoV-2 is simple: It suggests that the virus started out in an animal—probably a bat—that came into contact with a human. Boom, infected. At that point, the virus immediately began to spread to other humans.

The WHO report cites strong evidence showing that most coronaviruses that infect humans come from animals, including the virus that caused the SARS epidemic in 2003. Bats are thought to be the most likely culprits, as they host a virus that is genetically related to SARS-CoV-2.

The report acknowledges the possibility that the virus spread to humans from pangolins or minks. But David Robertson, head of viral genomics and bioinformatics at the University of Glasgow, says the WHO joint team sampled many animal species beyond bats for the report. The analyses points to bats as the reservoir species.

“So what you have to worry about then is how did it get from bats to humans?” Robertson says. “Did somebody go into an area, get infected, and then get a train to Wuhan?”

Direct transmission between bats and humans is possible: Studies have shown that people who live near bat caves in southern China’s Yunnan Province have antibodies to bat coronaviruses. But most humans generally don’t spend much time around bats, unless they are bat scientists (who typically wear protective equipment). So it’s unclear why, if the virus jumped from bats directly to humans, the first outbreak would have occurred in Wuhan, a thousand miles away from the bat caves of Yunnan.

Furthermore, the report notes that it would take decades for even the closely related bat coronavirus to evolve into SARS-CoV-2. Since scientists haven’t found a bat virus that would provide the missing link, the WHO team assessed this theory as “possible to likely.”

2. Spillover from animals to humans through an intermediate host

WHO ASSESSMENT: likely to very likely

In the absence of a smoking gun showing that bats passed the virus directly to humans, scientists believe the more likely theory is that the virus first traveled through another animal, such as a mink or a pangolin. Unlike bats, these animals have regular contact with humans—particularly if they’re being raised on a farm or trafficked in the illegal wildlife trade.

If the virus jumped first to another animal, that might also explain how it adapted to be harmful to humans—although Robertson says that the virus likely wouldn’t have had to change much. Genomic analyses suggest that SARS-CoV-2 is a generalist virus rather than one specifically adapted to humans, explaining why it can easily jump among pangolins, mink, cats, and other species.

The WHO report points out that this is the path that previous coronaviruses have taken to infect humans. The SARS virus, for example, is thought to have passed from bats to palm civets before causing a human epidemic in 2002. Meanwhile, the virus that causes MERS has been found in dromedary camels throughout the Middle East.

Daniel Lucey, an adjunct professor of infectious diseases at Georgetown University Medical Center, says that the similarities between SARS-CoV-2 and its relatives SARS and MERS is a compelling argument that it might have started out the same way.

“Now we have three coronaviruses that cause pneumonia and systemic illness and death,” he says. “Past is prologue.”

But, if the theory holds true, it’s not clear what that intermediary animal might have been for SARS-CoV-2. The WHO team analyzed samples from thousands of farmed animals across China, all of which tested negative for the virus. Lucey argues that the WHO team didn’t adequately test China’s farmed mink—one of the suspected intermediaries—but Rasmussen says the report itself acknowledges that it only scratches the surface.

“That’s a fraction of the animals that are farmed or captured or transported for this purpose in China,” she says. “I think we haven’t done anywhere near enough sampling.”

3. Introduction through refrigerated or frozen foods


Another theory holds that the virus may have come to humans through what’s known as the cold chain—the supply line for distributing frozen and refrigerated foods. In this scenario, the virus might have actually originated outside of China but was imported either on the surface of food packaging or in the food itself.

This theory gained traction last summer after a couple of outbreaks in China, and there has since been some evidence suggesting that pathogens can survive longer in cold temperatures.

Still, while the cold chain might have played a role in new outbreaks, scientists say there’s little reason to believe that it was the source of the pandemic. There’s no direct evidence that SARS-CoV-2 is responsible for foodborne outbreaks, while Rasmussen notes that COVID-19 rarely spreads through surfaces—which was good news for those weary of wiping down their groceries.

“It’s not impossible,” she says. “You can’t rule it out. But I don’t think the evidence base is particularly strong for that.”

Rasmussen says a more plausible way that the virus might spread through the food chain would be through wildlife that’s farmed for human consumption. But, she points out, that bleeds over into the territory of the theory for an intermediate host.

Some critics claim that this theory is a red herring to push suspicion from China and onto other countries. Lucey considers this pathway the least likely of the four the joint team identified, arguing it’s implausible that the virus would have stayed viable on the packaging for as long as it took to import from Europe or elsewhere. He also questions why these infections would have turned up in Wuhan and nowhere else.

“To me, it’s beyond far-fetched,” he says.

4. Laboratory leak

WHO ASSESSMENT: extremely unlikely

The most controversial hypothesis for the origin of SARS-CoV-2 is also the one that most scientists agree is the least likely: that the virus somehow leaked out of a laboratory in Wuhan where researchers study bat coronaviruses. Originally promulgated by former President Donald Trump and his administration, this theory suggests that perhaps a researcher was infected in the lab—accidentally or otherwise—or manipulated a coronavirus strain to create SARS-CoV-2.

Although there have been laboratory leaks in the past, the WHO report points out that they’re rare. The main evidence it cites to support this theory is the fact that researchers at the Wuhan Institute of Virology have sequenced the bat coronavirus strain—called CoV RaTG13, which is 96.2 percent similar to SARS-CoV-2, and its closest known relative—as part of their effort to prevent zoonotic viruses from spilling over to humans. A laboratory run by the Wuhan Center for Disease Control and Prevention has also worked with bat coronaviruses.

But that’s just about the only evidence that supports this hypothesis. The WHO report says there is no record that any Wuhan laboratory was working with a virus more closely related to SARS-CoV-2 before the first cases of COVID-19 were diagnosed in December 2019, nor did any laboratory staff report any COVID-like symptoms suggesting that they had been infected. But scientists point out that the evidence both for and against the lab leak hypothesis is thin.

Lucey believes the lab leak theory is plausible, though less likely than zoonotic transmission, given the lack of evidence. He points out that there was no forensic investigation of the labs in Wuhan, and he questions why the WHO authorized the team to investigate the lab at all without the mandate to conduct such an investigation or team members with the subject-matter expertise to carry it out.

“There’s not really any way to prove or disprove the lab leak theory based on what’s been presented in this report,” Rasmussen agrees, noting that to put the matter to rest there would need to be a forensic audit of lab records to look for the ancestral virus to SARS-COV-2. “But my opinion is that the lab leak theory, while not impossible, is less likely to be the explanation.”

Rasmussen explains that there’s no evidence that SARS-CoV-2 is the result of genetic manipulation, nor is it likely that it could have been created by accident. It’s incredibly difficult to culture a virus that’s strong enough to cause human infections from a bat sample, she says. Meanwhile, similar viruses commonly occur in nature, making that the far likelier source.

Robertson says that supporters of the lab leak theory argue that SARS-CoV-2 has traveled too quickly and efficiently through the human population to be natural in origin. But if the virus is a generalist, as genomic studies show, he says it’s not surprising that it is so effective at infecting humans.

“I think the evidence is pretty good that it didn’t have to change much to be successful in humans,” he says.

A research roadmap

Although the WHO report may not have shed much light on the origins of SARS-CoV-2, Robertson says this is just the beginning of what can sometimes be a long process. But he says there’s a public health imperative now to launch more rigorous follow-up studies.

“There’s a virus somewhere out there that’s very close to SARS-CoV-2,” he says. “That seems to be the bit that’s terrifying.”

Rasmussen says that the WHO report lays out a roadmap for further studies to discover the origins of the virus. It recommends better surveillance of captive and farmed animals to determine potential reservoir or intermediate hosts, as well as more sampling among bats—both in China and beyond, as there is also evidence of related coronaviruses circulating in regions such as Southeast Asia. The report also recommends in-depth epidemiological studies of the first COVID-19 cases.

Understanding how an outbreak got started helps scientists and governments pinpoint how to strengthen protections—whether that’s more rigorous surveillance for infections in animals and the food chain, or tighter biosafety protocols in laboratories.

“There’s a popular perception that we need some kind of justice or explanation, and somebody needs to answer for this pandemic,” Rasmussen says. “But the real reason why we need to figure out the origin is so that it can inform our efforts to prevent another pandemic like this from happening.”

The Science suggests Wuhan Lab leak

(update 6/13/2021)

The COVID-19 pathogen has a genetic footprint that has never ben observed in a natural coronavirus. “Now the damning fact. It was the sequence that appears in CoV-2. Proponents of Zoonotic origin must explain why the novel coronavirus, when it mutates or recombines is supposed to pick its least favorite combination, the double CGG. Why did it replicate the choice the labs’ gain of function researchers would have made?”

“When the abs Shi Zhengli and colleagues published a paper in February 2020 with the viruses’ partial genome, they omitted any mention of the special sequence that supercharges the virus or the double CGG section.”


“Why was the US Department of Defense funding bioweapons research in Wuhan? “PREDICT awarded $200 million in grants before grant funding ran out and President Trump ended the program…of the $200 million, $63 million–nearly one-third of all PREDICT grant funds–went to Ecohealth Alliance.”

Becker News

Chinagate: Wuhan labs “Secret military activity led to February 2020 covid vaccine patent, Report finds. “The plot thickens, one of the scientists involved in the research, Zhon Yusen, was the subject of an unexplained death in May 2020 after a probe into the origins of the COVID-19 had begun.”

COVID-19 Testing Fiasco Timetable

(update 3/18/2021)

+ January 11: China Posts virus genome online

+ Mid-January: Germany develops test

+ Mid-January: WHO adopts Germany’s test

+January 23 Australia announces test

+January 24 CDC announces own test

+February 5: first CDC tests are shipped

+February 12: CDC announces tests are faulty

+February 29: FDA makes it easier for others to develop tests

The origin of COVID: Did people or nature open Pandora’s box at Wuhan?

(Update 5/9/2021)

Members of the World Health Organization (WHO) team investigating the origins of the COVID-19 coronavirus arrive by car at the Wuhan Institute of Virology on February 3. (Photo by HECTOR RETAMAL/AFP via Getty Images) Members of the World Health Organization (WHO) team investigating the origins of the COVID-19 coronavirus arrive by car at the Wuhan Institute of Virology on February 3.

The COVID-19 pandemic has disrupted lives the world over for more than a year. Its death toll will soon reach three million people. Yet the origin of pandemic remains uncertain: The political agendas of governments and scientists have generated thick clouds of obfuscation, which the mainstream press seems helpless to dispel.

In what follows I will sort through the available scientific facts, which hold many clues as to what happened, and provide readers with the evidence to make their own judgments. I will then try to assess the complex issue of blame, which starts with, but extends far beyond, the government of China.

By the end of this article, you may have learned a lot about the molecular biology of viruses. I will try to keep this process as painless as possible. But the science cannot be avoided because for now, and probably for a long time hence, it offers the only sure thread through the maze.

The virus that caused the pandemic is known officially as SARS-CoV-2, but can be called SARS2 for short. As many people know, there are two main theories about its origin. One is that it jumped naturally from wildlife to people. The other is that the virus was under study in a lab, from which it escaped. It matters a great deal which is the case if we hope to prevent a second such occurrence.

I’ll describe the two theories, explain why each is plausible, and then ask which provides the better explanation of the available facts. It’s important to note that so far there is no direct evidence for either theory. Each depends on a set of reasonable conjectures but so far lacks proof. So I have only clues, not conclusions, to offer. But those clues point in a specific direction. And having inferred that direction, I’m going to delineate some of the strands in this tangled skein of disaster.

A tale of two theories. After the pandemic first broke out in December 2019, Chinese authorities reported that many cases had occurred in the wet market — a place selling wild animals for meat — in Wuhan. This reminded experts of the SARS1 epidemic of 2002, in which a bat virus had spread first to civets, an animal sold in wet markets, and from civets to people. A similar bat virus caused a second epidemic, known as MERS, in 2012. This time the intermediary host animal was camels.

The decoding of the virus’s genome showed it belonged a viral family known as beta-coronaviruses, to which the SARS1 and MERS viruses also belong. The relationship supported the idea that, like them, it was a natural virus that had managed to jump from bats, via another animal host, to people. The wet market connection, the major point of similarity with the SARS1 and MERS epidemics, was soon broken: Chinese researchers found earlier cases in Wuhan with no link to the wet market. But that seemed not to matter when so much further evidence in support of natural emergence was expected shortly.

Wuhan, however, is home of the Wuhan Institute of Virology, a leading world center for research on coronaviruses. So the possibility that the SARS2 virus had escaped from the lab could not be ruled out. Two reasonable scenarios of origin were on the table.

From early on, public and media perceptions were shaped in favor of the natural emergence scenario by strong statements from two scientific groups. These statements were not at first examined as critically as they should have been.

“We stand together to strongly condemn conspiracy theories suggesting that COVID-19 does not have a natural origin,” a group of virologists and others wrote in the Lancet on February 19, 2020, when it was really far too soon for anyone to be sure what had happened. Scientists “overwhelmingly conclude that this coronavirus originated in wildlife,” they said, with a stirring rallying call for readers to stand with Chinese colleagues on the frontline of fighting the disease.

Contrary to the letter writers’ assertion, the idea that the virus might have escaped from a lab invoked accident, not conspiracy. It surely needed to be explored, not rejected out of hand. A defining mark of good scientists is that they go to great pains to distinguish between what they know and what they don’t know. By this criterion, the signatories of the Lancet letter were behaving as poor scientists: They were assuring the public of facts they could not know for sure were true.

It later turned out that the Lancet letter had been organized and drafted by Peter Daszak, president of the EcoHealth Alliance of New York. Daszak’s organization funded coronavirus research at the Wuhan Institute of Virology. If the SARS2 virus had indeed escaped from research he funded, Daszak would be potentially culpable. This acute conflict of interest was not declared to the Lancet’s readers. To the contrary, the letter concluded, “We declare no competing interests.”

Virologists like Daszak had much at stake in the assigning of blame for the pandemic. For 20 years, mostly beneath the public’s attention, they had been playing a dangerous game. In their laboratories they routinely created viruses more dangerous than those that exist in nature. They argued that they could do so safely, and that by getting ahead of nature they could predict and prevent natural “spillovers,” the cross-over of viruses from an animal host to people. If SARS2 had indeed escaped from such a laboratory experiment, a savage blowback could be expected, and the storm of public indignation would affect virologists everywhere, not just in China. “It would shatter the scientific edifice top to bottom,” an MIT Technology Review editor, Antonio Regalado, said in March 2020.

A second statement that had enormous influence in shaping public attitudes was a letter (in other words an opinion piece, not a scientific article) published on 17 March 2020 in the journal Nature Medicine. Its authors were a group of virologists led by Kristian G. Andersen of the Scripps Research Institute. “Our analyses clearly show that SARS-CoV-2 is not a laboratory construct or a purposefully manipulated virus,” the five virologists declared in the second paragraph of their letter.

Unfortunately, this was another case of poor science, in the sense defined above. True, some older methods of cutting and pasting viral genomes retain tell-tale signs of manipulation. But newer methods, called “no-see-um” or “seamless” approaches, leave no defining marks. Nor do other methods for manipulating viruses such as serial passage, the repeated transfer of viruses from one culture of cells to another. If a virus has been manipulated, whether with a seamless method or by serial passage, there is no way of knowing that this is the case. Andersen and his colleagues were assuring their readers of something they could not know.

The discussion part of their letter begins, “It is improbable that SARS-CoV-2 emerged through laboratory manipulation of a related SARS-CoV-like coronavirus.” But wait, didn’t the lead say the virus had clearly not been manipulated? The authors’ degree of certainty seemed to slip several notches when it came to laying out their reasoning.

The reason for the slippage is clear once the technical language has been penetrated. The two reasons the authors give for supposing manipulation to be improbable are decidedly inconclusive.

First, they say that the spike protein of SARS2 binds very well to its target, the human ACE2 receptor, but does so in a different way from that which physical calculations suggest would be the best fit. Therefore the virus must have arisen by natural selection, not manipulation.

If this argument seems hard to grasp, it’s because it’s so strained. The authors’ basic assumption, not spelt out, is that anyone trying to make a bat virus bind to human cells could do so in only one way. First they would calculate the strongest possible fit between the human ACE2 receptor and the spike protein with which the virus latches onto it. They would then design the spike protein accordingly (by selecting the right string of amino acid units that compose it). Since the SARS2 spike protein is not of this calculated best design, the Andersen paper says, therefore it can’t have been manipulated.

But this ignores the way that virologists do in fact get spike proteins to bind to chosen targets, which is not by calculation but by splicing in spike protein genes from other viruses or by serial passage. With serial passage, each time the virus’s progeny are transferred to new cell cultures or animals, the more successful are selected until one emerges that makes a really tight bind to human cells. Natural selection has done all the heavy lifting. The Andersen paper’s speculation about designing a viral spike protein through calculation has no bearing on whether or not the virus was manipulated by one of the other two methods.

The authors’ second argument against manipulation is even more contrived. Although most living things use DNA as their hereditary material, a number of viruses use RNA, DNA’s close chemical cousin. But RNA is difficult to manipulate, so researchers working on coronaviruses, which are RNA-based, will first convert the RNA genome to DNA. They manipulate the DNA version, whether by adding or altering genes, and then arrange for the manipulated DNA genome to be converted back into infectious RNA.

Only a certain number of these DNA backbones have been described in the scientific literature. Anyone manipulating the SARS2 virus “would probably” have used one of these known backbones, the Andersen group writes, and since SARS2 is not derived from any of them, therefore it was not manipulated. But the argument is conspicuously inconclusive. DNA backbones are quite easy to make, so it’s obviously possible that SARS2 was manipulated using an unpublished DNA backbone.

And that’s it. These are the two arguments made by the Andersen group in support of their declaration that the SARS2 virus was clearly not manipulated. And this conclusion, grounded in nothing but two inconclusive speculations, convinced the world’s press that SARS2 could not have escaped from a lab. A technical critique of the Andersen letter takes it down in harsher words.

Science is supposedly a self-correcting community of experts who constantly check each other’s work. So why didn’t other virologists point out that the Andersen group’s argument was full of absurdly large holes? Perhaps because in today’s universities speech can be very costly. Careers can be destroyed for stepping out of line. Any virologist who challenges the community’s declared view risks having his next grant application turned down by the panel of fellow virologists that advises the government grant distribution agency.

The Daszak and Andersen letters were really political, not scientific, statements, yet were amazingly effective. Articles in the mainstream press repeatedly stated that a consensus of experts had ruled lab escape out of the question or extremely unlikely. Their authors relied for the most part on the Daszak and Andersen letters, failing to understand the yawning gaps in their arguments. Mainstream newspapers all have science journalists on their staff, as do the major networks, and these specialist reporters are supposed to be able to question scientists and check their assertions. But the Daszak and Andersen assertions went largely unchallenged.

Doubts about natural emergence. Natural emergence was the media’s preferred theory until around February 2021 and the visit by a World Health Organization (WHO) commission to China. The commission’s composition and access were heavily controlled by the Chinese authorities. Its members, who included the ubiquitous Daszak, kept asserting before, during, and after their visit that lab escape was extremely unlikely. But this was not quite the propaganda victory the Chinese authorities may have been hoping for. What became clear was that the Chinese had no evidence to offer the commission in support of the natural emergence theory.

This was surprising because both the SARS1 and MERS viruses had left copious traces in the environment. The intermediary host species of SARS1 was identified within four months of the epidemic’s outbreak, and the host of MERS within nine months. Yet some 15 months after the SARS2 pandemic began, and after a presumably intensive search, Chinese researchers had failed to find either the original bat population, or the intermediate species to which SARS2 might have jumped, or any serological evidence that any Chinese population, including that of Wuhan, had ever been exposed to the virus prior to December 2019. Natural emergence remained a conjecture which, however plausible to begin with, had gained not a shred of supporting evidence in over a year.

And as long as that remains the case, it’s logical to pay serious attention to the alternative conjecture, that SARS2 escaped from a lab.

Why would anyone want to create a novel virus capable of causing a pandemic? Ever since virologists gained the tools for manipulating a virus’s genes, they have argued they could get ahead of a potential pandemic by exploring how close a given animal virus might be to making the jump to humans. And that justified lab experiments in enhancing the ability of dangerous animal viruses to infect people, virologists asserted.

With this rationale, they have recreated the 1918 flu virus, shown how the almost extinct polio virus can be synthesized from its published DNA sequence, and introduced a smallpox gene into a related virus.

These enhancements of viral capabilities are known blandly as gain-of-function experiments. With coronaviruses, there was particular interest in the spike proteins, which jut out all around the spherical surface of the virus and pretty much determine which species of animal it will target. In 2000 Dutch researchers, for instance, earned the gratitude of rodents everywhere by genetically engineering the spike protein of a mouse coronavirus so that it would attack only cats.

The spike proteins on the coronavirus’s surface determine which animal it can infect. Image credit:

Virologists started studying bat coronaviruses in earnest after these turned out to be the source of both the SARS1 and MERS epidemics. In particular, researchers wanted to understand what changes needed to occur in a bat virus’s spike proteins before it could infect people.

Researchers at the Wuhan Institute of Virology, led by China’s leading expert on bat viruses, Shi Zheng-li or “Bat Lady,” mounted frequent expeditions to the bat-infested caves of Yunnan in southern China and collected around a hundred different bat coronaviruses.

Shi then teamed up with Ralph S. Baric, an eminent coronavirus researcher at the University of North Carolina. Their work focused on enhancing the ability of bat viruses to attack humans so as to “examine the emergence potential (that is, the potential to infect humans) of circulating bat CoVs [coronaviruses].” In pursuit of this aim, in November 2015 they created a novel virus by taking the backbone of the SARS1 virus and replacing its spike protein with one from a bat virus (known as SHC014-CoV). This manufactured virus was able to infect the cells of the human airway, at least when tested against a lab culture of such cells.

The SHC014-CoV/SARS1 virus is known as a chimera because its genome contains genetic material from two strains of virus. If the SARS2 virus were to have been cooked up in Shi’s lab, then its direct prototype would have been the SHC014-CoV/SARS1 chimera, the potential danger of which concerned many observers and prompted intense discussion.

“If the virus escaped, nobody could predict the trajectory,” said Simon Wain-Hobson, a virologist at the Pasteur Institute in Paris.

Baric and Shi referred to the obvious risks in their paper but argued they should be weighed against the benefit of foreshadowing future spillovers. Scientific review panels, they wrote, “may deem similar studies building chimeric viruses based on circulating strains too risky to pursue.” Given various restrictions being placed on gain-of function (GOF) research, matters had arrived in their view at “a crossroads of GOF research concerns; the potential to prepare for and mitigate future outbreaks must be weighed against the risk of creating more dangerous pathogens. In developing policies moving forward, it is important to consider the value of the data generated by these studies and whether these types of chimeric virus studies warrant further investigation versus the inherent risks involved.”

That statement was made in 2015. From the hindsight of 2021, one can say that the value of gain-of-function studies in preventing the SARS2 epidemic was zero. The risk was catastrophic, if indeed the SARS2 virus was generated in a gain-of-function experiment.

Inside the Wuhan Institute of Virology. Baric had developed, and taught Shi, a general method for engineering bat coronaviruses to attack other species. The specific targets were human cells grown in cultures and humanized mice. These laboratory mice, a cheap and ethical stand-in for human subjects, are genetically engineered to carry the human version of a protein called ACE2 that studs the surface of cells that line the airways.

Shi returned to her lab at the Wuhan Institute of Virology and resumed the work she had started on genetically engineering coronaviruses to attack human cells. How can we be so sure?

Because, by a strange twist in the story, her work was funded by the National Institute of Allergy and Infectious Diseases (NIAID), a part of the US National Institutes of Health (NIH). And grant proposals that funded her work, which are a matter of public record, specify exactly what she planned to do with the money.

The grants were assigned to the prime contractor, Daszak of the EcoHealth Alliance, who subcontracted them to Shi. Here are extracts from the grants for fiscal years 2018 and 2019. (“CoV” stands for coronavirus and “S protein” refers to the virus’s spike protein.)

“Test predictions of CoV inter-species transmission. Predictive models of host range (i.e. emergence potential) will be tested experimentally using reverse genetics, pseudovirus and receptor binding assays, and virus infection experiments across a range of cell cultures from different species and humanized mice.

“We will use S protein sequence data, infectious clone technology, in vitro and in vivo infection experiments and analysis of receptor binding to test the hypothesis that % divergence thresholds in S protein sequences predict spillover potential.”

What this means, in non-technical language, is that Shi set out to create novel coronaviruses with the highest possible infectivity for human cells. Her plan was to take genes that coded for spike proteins possessing a variety of measured affinities for human cells, ranging from high to low. She would insert these spike genes one by one into the backbone of a number of viral genomes (“reverse genetics” and “infectious clone technology”), creating a series of chimeric viruses. These chimeric viruses would then be tested for their ability to attack human cell cultures (“in vitro”) and humanized mice (“in vivo”). And this information would help predict the likelihood of “spillover,” the jump of a coronavirus from bats to people.

The methodical approach was designed to find the best combination of coronavirus backbone and spike protein for infecting human cells. The approach could have generated SARS2-like viruses, and indeed may have created the SARS2 virus itself with the right combination of virus backbone and spike protein.

It cannot yet be stated that Shi did or did not generate SARS2 in her lab because her records have been sealed, but it seems she was certainly on the right track to have done so. “It is clear that the Wuhan Institute of Virology was systematically constructing novel chimeric coronaviruses and was assessing their ability to infect human cells and human-ACE2-expressing mice,” says Richard H. Ebright, a molecular biologist at Rutgers University and leading expert on biosafety.

“It is also clear,” Ebright said, “that, depending on the constant genomic contexts chosen for analysis, this work could have produced SARS-CoV-2 or a proximal progenitor of SARS-CoV-2.” “Genomic context” refers to the particular viral backbone used as the testbed for the spike protein.

The lab escape scenario for the origin of the SARS2 virus, as should by now be evident, is not mere hand-waving in the direction of the Wuhan Institute of Virology. It is a detailed proposal, based on the specific project being funded there by the NIAID.

Even if the grant required the work plan described above, how can we be sure that the plan was in fact carried out? For that we can rely on the word of Daszak, who has been much protesting for the last 15 months that lab escape was a ludicrous conspiracy theory invented by China-bashers.

On December 9, 2019, before the outbreak of the pandemic became generally known, Daszak gave an interview in which he talked in glowing terms of how researchers at the Wuhan Institute of Virology had been reprogramming the spike protein and generating chimeric coronaviruses capable of infecting humanized mice.

“And we have now found, you know, after 6 or 7 years of doing this, over 100 new SARS-related coronaviruses, very close to SARS,” Daszak says around minute 28 of the interview. “Some of them get into human cells in the lab, some of them can cause SARS disease in humanized mice models and are untreatable with therapeutic monoclonals and you can’t vaccinate against them with a vaccine. So, these are a clear and present danger….RELATED:Uncanceled: Banned from Facebook, Trump reaches millions on TV

“Interviewer: You say these are diverse coronaviruses and you can’t vaccinate against them, and no anti-virals — so what do we do?

“Daszak: Well I think…coronaviruses — you can manipulate them in the lab pretty easily. Spike protein drives a lot of what happen with coronavirus, in zoonotic risk. So you can get the sequence, you can build the protein, and we work a lot with Ralph Baric at UNC to do this. Insert into the backbone of another virus and do some work in the lab. So you can get more predictive when you find a sequence. You’ve got this diversity. Now the logical progression for vaccines is, if you are going to develop a vaccine for SARS, people are going to use pandemic SARS, but let’s insert some of these other things and get a better vaccine.” The insertions he referred to perhaps included an element called the furin cleavage site, discussed below, which greatly increases viral infectivity for human cells.

In disjointed style, Daszak is referring to the fact that once you have generated a novel coronavirus that can attack human cells, you can take the spike protein and make it the basis for a vaccine.

One can only imagine Daszak’s reaction when he heard of the outbreak of the epidemic in Wuhan a few days later. He would have known better than anyone the Wuhan Institute’s goal of making bat coronaviruses infectious to humans, as well as the weaknesses in the institute’s defense against their own researchers becoming infected.

But instead of providing public health authorities with the plentiful information at his disposal, he immediately launched a public relations campaign to persuade the world that the epidemic couldn’t possibly have been caused by one of the institute’s souped-up viruses. “The idea that this virus escaped from a lab is just pure baloney. It’s simply not true,” he declared in an April 2020 interview.

The safety arrangements at the Wuhan Institute of Virology. Daszak was possibly unaware of, or perhaps he knew all too well, the long history of viruses escaping from even the best run laboratories. The smallpox virus escaped three times from labs in England in the 1960’s and 1970’s, causing 80 cases and 3 deaths. Dangerous viruses have leaked out of labs almost every year since. Coming to more recent times, the SARS1 virus has proved a true escape artist, leaking from laboratories in Singapore, Taiwan, and no less than four times from the Chinese National Institute of Virology in Beijing.

One reason for SARS1 being so hard to handle is that there were no vaccines available to protect laboratory workers. As Daszak mentioned in the December 19 interview quoted above, the Wuhan researchers too had been unable to develop vaccines against the coronaviruses they had designed to infect human cells. They would have been as defenseless against the SARS2 virus, if it were generated in their lab, as their Beijing colleagues were against SARS1.

A second reason for the severe danger of novel coronaviruses has to do with the required levels of lab safety. There are four degrees of safety, designated BSL1 to BSL4, with BSL4 being the most restrictive and designed for deadly pathogens like the Ebola virus.

The Wuhan Institute of Virology had a new BSL4 lab, but its state of readiness considerably alarmed the State Department inspectors who visited it from the Beijing embassy in 2018. “The new lab has a serious shortage of appropriately trained technicians and investigators needed to safely operate this high-containment laboratory,” the inspectors wrote in a cable of January 19, 2018.

The real problem, however, was not the unsafe state of the Wuhan BSL4 lab but the fact that virologists worldwide don’t like working in BSL4 conditions. You have to wear a space suit, do operations in closed cabinets, and accept that everything will take twice as long. So the rules assigning each kind of virus to a given safety level were laxer than some might think was prudent.

Before 2020, the rules followed by virologists in China and elsewhere required that experiments with the SARS1 and MERS viruses be conducted in BSL3 conditions. But all other bat coronaviruses could be studied in BSL2, the next level down. BSL2 requires taking fairly minimal safety precautions, such as wearing lab coats and gloves, not sucking up liquids in a pipette, and putting up biohazard warning signs. Yet a gain-of-function experiment conducted in BSL2 might produce an agent more infectious than either SARS1 or MERS. And if it did, then lab workers would stand a high chance of infection, especially if unvaccinated.

Much of Shi’s work on gain-of-function in coronaviruses was performed at the BSL2 safety level, as is stated in her publications and other documents. She has said in an interview with Science magazine that “[t]he coronavirus research in our laboratory is conducted in BSL-2 or BSL-3 laboratories.”

“It is clear that some or all of this work was being performed using a biosafety standard — biosafety level 2, the biosafety level of a standard US dentist’s office — that would pose an unacceptably high risk of infection of laboratory staff upon contact with a virus having the transmission properties of SARS-CoV-2,” Ebright says.

“It also is clear,” he adds, “that this work never should have been funded and never should have been performed.”

This is a view he holds regardless of whether or not the SARS2 virus ever saw the inside of a lab.

Concern about safety conditions at the Wuhan lab was not, it seems, misplaced. According to a fact sheet issued by the State Department on January 15, 2021, “The U.S. government has reason to believe that several researchers inside the WIV became sick in autumn 2019, before the first identified case of the outbreak, with symptoms consistent with both COVID-19 and common seasonal illnesses.”

David Asher, a fellow of the Hudson Institute and former consultant to the State Department, provided more detail about the incident at a seminar. Knowledge of the incident came from a mix of public information and “some high end information collected by our intelligence community,” he said. Three people working at a BSL3 lab at the institute fell sick within a week of each other with severe symptoms that required hospitalization. This was “the first known cluster that we’re aware of, of victims of what we believe to be COVID-19.” Influenza could not completely be ruled out but seemed unlikely in the circumstances, he said.

Comparing the rival scenarios of SARS2 origin. The evidence above adds up to a serious case that the SARS2 virus could have been created in a lab, from which it then escaped. But the case, however substantial, falls short of proof. Proof would consist of evidence from the Wuhan Institute of Virology, or related labs in Wuhan, that SARS2 or a predecessor virus was under development there. For lack of access to such records, another approach is to take certain salient facts about the SARS2 virus and ask how well each is explained by the two rival scenarios of origin, those of natural emergence and lab escape. Here are four tests of the two hypotheses. A couple have some technical detail, but these are among the most persuasive for those who may care to follow the argument.

1) The place of origin. Start with geography. The two closest known relatives of the SARS2 virus were collected from bats living in caves in Yunnan, a province of southern China. If the SARS2 virus had first infected people living around the Yunnan caves, that would strongly support the idea that the virus had spilled over to people naturally. But this isn’t what happened. The pandemic broke out 1,500 kilometers away, in Wuhan.

Beta-coronaviruses, the family of bat viruses to which SARS2 belongs, infect the horseshoe bat Rhinolophus affinis, which ranges across southern China. The bats’ range is 50 kilometers, so it’s unlikely that any made it to Wuhan. In any case, the first cases of the COVID-19 pandemic probably occurred in September, when temperatures in Hubei province are already cold enough to send bats into hibernation.

What if the bat viruses infected some intermediate host first? You would need a longstanding population of bats in frequent proximity with an intermediate host, which in turn must often cross paths with people. All these exchanges of virus must take place somewhere outside Wuhan, a busy metropolis which so far as is known is not a natural habitat of Rhinolophus bat colonies. The infected person (or animal) carrying this highly transmissible virus must have traveled to Wuhan without infecting anyone else. No one in his or her family got sick. If the person jumped on a train to Wuhan, no fellow passengers fell ill.

It’s a stretch, in other words, to get the pandemic to break out naturally outside Wuhan and then, without leaving any trace, to make its first appearance there.

For the lab escape scenario, a Wuhan origin for the virus is a no-brainer. Wuhan is home to China’s leading center of coronavirus research where, as noted above, researchers were genetically engineering bat coronaviruses to attack human cells. They were doing so under the minimal safety conditions of a BSL2 lab. If a virus with the unexpected infectiousness of SARS2 had been generated there, its escape would be no surprise.

2) Natural history and evolution. The initial location of the pandemic is a small part of a larger problem, that of its natural history. Viruses don’t just make one time jumps from one species to another. The coronavirus spike protein, adapted to attack bat cells, needs repeated jumps to another species, most of which fail, before it gains a lucky mutation. Mutation — a change in one of its RNA units — causes a different amino acid unit to be incorporated into its spike protein and makes the spike protein better able to attack the cells of some other species.

Through several more such mutation-driven adjustments, the virus adapts to its new host, say some animal with which bats are in frequent contact. The whole process then resumes as the virus moves from this intermediate host to people.

In the case of SARS1, researchers have documented the successive changes in its spike protein as the virus evolved step by step into a dangerous pathogen. After it had gotten from bats into civets, there were six further changes in its spike protein before it became a mild pathogen in people. After a further 14 changes, the virus was much better adapted to humans, and with a further four, the epidemic took off.

But when you look for the fingerprints of a similar transition in SARS2, a strange surprise awaits. The virus has changed hardly at all, at least until recently. From its very first appearance, it was well adapted to human cells. Researchers led by Alina Chan of the Broad Institute compared SARS2 with late stage SARS1, which by then was well adapted to human cells, and found that the two viruses were similarly well adapted. “By the time SARS-CoV-2 was first detected in late 2019, it was already pre-adapted to human transmission to an extent similar to late epidemic SARS-CoV,” they wrote.

Even those who think lab origin unlikely agree that SARS2 genomes are remarkably uniform. Baric writes that “early strains identified in Wuhan, China, showed limited genetic diversity, which suggests that the virus may have been introduced from a single source.”

A single source would of course be compatible with lab escape, less so with the massive variation and selection which is evolution’s hallmark way of doing business.

The uniform structure of SARS2 genomes gives no hint of any passage through an intermediate animal host, and no such host has been identified in nature.

Proponents of natural emergence suggest that SARS2 incubated in a yet-to-be found human population before gaining its special properties. Or that it jumped to a host animal outside China.

All these conjectures are possible, but strained. Proponents of a lab leak have a simpler explanation. SARS2 was adapted to human cells from the start because it was grown in humanized mice or in lab cultures of human cells, just as described in Daszak’s grant proposal. Its genome shows little diversity because the hallmark of lab cultures is uniformity.

Proponents of laboratory escape joke that of course the SARS2 virus infected an intermediary host species before spreading to people, and that they have identified it — a humanized mouse from the Wuhan Institute of Virology.

3) The furin cleavage site. The furin cleavage site is a minute part of the virus’s anatomy but one that exerts great influence on its infectivity. It sits in the middle of the SARS2 spike protein. It also lies at the heart of the puzzle of where the virus came from.

The spike protein has two sub-units with different roles. The first, called S1, recognizes the virus’s target, a protein called angiotensin converting enzyme-2 (or ACE2) which studs the surface of cells lining the human airways. The second, S2, helps the virus, once anchored to the cell, to fuse with the cell’s membrane. After the virus’s outer membrane has coalesced with that of the stricken cell, the viral genome is injected into the cell, hijacks its protein-making machinery and forces it to generate new viruses.

But this invasion cannot begin until the S1 and S2 subunits have been cut apart. And there, right at the S1/S2 junction, is the furin cleavage site that ensures the spike protein will be cleaved in exactly the right place.

The virus, a model of economic design, does not carry its own cleaver. It relies on the cell to do the cleaving for it. Human cells have a protein cutting tool on their surface known as furin. Furin will cut any protein chain that carries its signature target cutting site. This is the sequence of amino acid units proline-arginine-arginine-alanine, or PRRA in the code that refers to each amino acid by a letter of the alphabet. PRRA is the amino acid sequence at the core of SARS2’s furin cleavage site.

Viruses have all kinds of clever tricks, so why does the furin cleavage site stand out? Because of all known SARS-related beta-coronaviruses, only SARS2 possesses a furin cleavage site. All the other viruses have their S2 unit cleaved at a different site and by a different mechanism.

How then did SARS2 acquire its furin cleavage site? Either the site evolved naturally, or it was inserted by researchers at the S1/S2 junction in a gain-of-function experiment.

Consider natural origin first. Two ways viruses evolve are by mutation and by recombination. Mutation is the process of random change in DNA (or RNA for coronaviruses) that usually results in one amino acid in a protein chain being switched for another. Many of these changes harm the virus but natural selection retains the few that do something useful. Mutation is the process by which the SARS1 spike protein gradually switched its preferred target cells from those of bats to civets, and then to humans.

Mutation seems a less likely way for SARS2’s furin cleavage site to be generated, even though it can’t completely be ruled out. The site’s four amino acid units are all together, and all at just the right place in the S1/S2 junction. Mutation is a random process triggered by copying errors (when new viral genomes are being generated) or by chemical decay of genomic units. So it typically affects single amino acids at different spots in a protein chain. A string of amino acids like that of the furin cleavage site is much more likely to be acquired all together through a quite different process known as recombination.

Recombination is an inadvertent swapping of genomic material that occurs when two viruses happen to invade the same cell, and their progeny are assembled with bits and pieces of RNA belonging to the other. Beta-coronaviruses will only combine with other beta-coronaviruses but can acquire, by recombination, almost any genetic element present in the collective genomic pool. What they cannot acquire is an element the pool does not possess. And no known SARS-related beta-coronavirus, the class to which SARS2 belongs, possesses a furin cleavage site.

Proponents of natural emergence say SARS2 could have picked up the site from some as yet unknown beta-coronavirus. But bat SARS-related beta-coronaviruses evidently don’t need a furin cleavage site to infect bat cells, so there’s no great likelihood that any in fact possesses one, and indeed none has been found so far.

The proponents’ next argument is that SARS2 acquired its furin cleavage site from people. A predecessor of SARS2 could have been circulating in the human population for months or years until at some point it acquired a furin cleavage site from human cells. It would then have been ready to break out as a pandemic.

If this is what happened, there should be traces in hospital surveillance records of the people infected by the slowly evolving virus. But none has so far come to light. According to the WHO report on the origins of the virus, the sentinel hospitals in Hubei province, home of Wuhan, routinely monitor influenza-like illnesses and “no evidence to suggest substantial SARSCoV-2 transmission in the months preceding the outbreak in December was observed.”

So it’s hard to explain how the SARS2 virus picked up its furin cleavage site naturally, whether by mutation or recombination.

That leaves a gain-of-function experiment. For those who think SARS2 may have escaped from a lab, explaining the furin cleavage site is no problem at all. “Since 1992 the virology community has known that the one sure way to make a virus deadlier is to give it a furin cleavage site at the S1/S2 junction in the laboratory,” writes Steven Quay, a biotech entrepreneur interested in the origins of SARS2. “At least 11 gain-of-function experiments, adding a furin site to make a virus more infective, are published in the open literature, including [by] Dr. Zhengli Shi, head of coronavirus research at the Wuhan Institute of Virology.”

4) A question of codons. There’s another aspect of the furin cleavage site that narrows the path for a natural emergence origin even further.

As everyone knows (or may at least recall from high school), the genetic code uses three units of DNA to specify each amino acid unit of a protein chain. When read in groups of 3, the 4 different kinds of DNA can specify 4 x 4 x 4 or 64 different triplets, or codons as they are called. Since there are only 20 kinds of amino acid, there are more than enough codons to go around, allowing some amino acids to be specified by more than one codon. The amino acid arginine, for instance, can be designated by any of the six codons CGU, CGC, CGA, CGG, AGA or AGG, where A, U, G and C stand for the four different kinds of unit in RNA.

Here’s where it gets interesting. Different organisms have different codon preferences. Human cells like to designate arginine with the codons CGT, CGC or CGG. But CGG is coronavirus’s least popular codon for arginine. Keep that in mind when looking at how the amino acids in the furin cleavage site are encoded in the SARS2 genome.

Now the functional reason why SARS2 has a furin cleavage site, and its cousin viruses don’t, can be seen by lining up (in a computer) the string of nearly 30,000 nucleotides in its genome with those of its cousin coronaviruses, of which the closest so far known is one called RaTG13. Compared with RaTG13, SARS2 has a 12-nucleotide insert right at the S1/S2 junction. The insert is the sequence T-CCT-CGG-CGG-GC. The CCT codes for proline, the two CGG’s for two arginines, and the GC is the beginning of a GCA codon that codes for alanine.

There are several curious features about this insert but the oddest is that of the two side-by-side CGG codons. Only 5 percent of SARS2’s arginine codons are CGG, and the double codon CGG-CGG has not been found in any other beta-coronavirus. So how did SARS2 acquire a pair of arginine codons that are favored by human cells but not by coronaviruses?

Proponents of natural emergence have an up-hill task to explain all the features of SARS2’s furin cleavage site. They have to postulate a recombination event at a site on the virus’s genome where recombinations are rare, and the insertion of a 12-nucleotide sequence with a double arginine codon unknown in the beta-coronavirus repertoire, at the only site in the genome that would significantly expand the virus’s infectivity.

“Yes, but your wording makes this sound unlikely — viruses are specialists at unusual events,” is the riposte of David L. Robertson, a virologist at the University of Glasgow who regards lab escape as a conspiracy theory. “Recombination is naturally very, very frequent in these viruses, there are recombination breakpoints in the spike protein and these codons appear unusual exactly because we’ve not sampled enough.”RELATED:Why choose a career in art over nuclear policy? The money

Robertson is correct that evolution is always producing results that may seem unlikely but in fact are not. Viruses can generate untold numbers of variants but we see only the one-in-a-billion that natural selection picks for survival. But this argument could be pushed too far. For instance, any result of a gain-of-function experiment could be explained as one that evolution would have arrived at in time. And the numbers game can be played the other way. For the furin cleavage site to arise naturally in SARS2, a chain of events has to happen, each of which is quite unlikely for the reasons given above. A long chain with several improbable steps is unlikely to ever be completed.

For the lab escape scenario, the double CGG codon is no surprise. The human-preferred codon is routinely used in labs. So anyone who wanted to insert a furin cleavage site into the virus’s genome would synthesize the PRRA-making sequence in the lab and would be likely to use CGG codons to do so.“When I first saw the furin cleavage site in the viral sequence, with its arginine codons, I said to my wife it was the smoking gun for the origin of the virus,” said David Baltimore, an eminent virologist and former president of CalTech. “These features make a powerful challenge to the idea of a natural origin for SARS2,” he said. [1]A third scenario of origin. There’s a variation on the natural emergence scenario that’s worth considering. This is the idea that SARS2 jumped directly from bats to humans, without going through an intermediate host as SARS1 and MERS did. A leading advocate is the virologist David Robertson who notes that SARS2 can attack several other species besides humans. He believes the virus evolved a generalist capability while still in bats. Because the bats it infects are widely distributed in southern and central China, the virus had ample opportunity to jump to people, even though it seems to have done so on only one known occasion. Robertson’s thesis explains why no one has so far found a trace of SARS2 in any intermediate host or in human populations surveilled before December 2019. It would also explain the puzzling fact that SARS2 has not changed since it first appeared in humans — it didn’t need to because it could already attack human cells efficiently.

One problem with this idea, though, is that if SARS2 jumped from bats to people in a single leap and hasn’t changed much since, it should still be good at infecting bats. And it seems it isn’t.

“Tested bat species are poorly infected by SARS-CoV-2 and they are therefore unlikely to be the direct source for human infection,” write a scientific group skeptical of natural emergence.

Still, Robertson may be onto something. The bat coronaviruses of the Yunnan caves can infect people directly. In April 2012 six miners clearing bat guano from the Mojiang mine contracted severe pneumonia with COVID-19-like symptoms and three eventually died. A virus isolated from the Mojiang mine, called RaTG13, is still the closest known relative of SARS2. Much mystery surrounds the origin, reporting and strangely low affinity of RaTG13 for bat cells, as well as the nature of 8 similar viruses that Shi reports she collected at the same time but has not yet published despite their great relevance to the ancestry of SARS2. But all that is a story for another time. The point here is that bat viruses can infect people directly, though only in special conditions.

So who else, besides miners excavating bat guano, comes into particularly close contact with bat coronaviruses? Well, coronavirus researchers do. Shi says she and her group collected more than 1,300 bat samples during some eight visits to the Mojiang cave between 2012 and 2015, and there were doubtless many expeditions to other Yunnan caves.

Imagine the researchers making frequent trips from Wuhan to Yunnan and back, stirring up bat guano in dark caves and mines, and now you begin to see a possible missing link between the two places. Researchers could have gotten infected during their collecting trips, or while working with the new viruses at the Wuhan Institute of Virology. The virus that escaped from the lab would have been a natural virus, not one cooked up by gain of function.

The direct-from-bats thesis is a chimera between the natural emergence and lab escape scenarios. It’s a possibility that can’t be dismissed. But against it are the facts that 1) both SARS2 and RaTG13 seem to have only feeble affinity for bat cells, so one can’t be fully confident that either ever saw the inside of a bat; and 2) the theory is no better than the natural emergence scenario at explaining how SARS2 gained its furin cleavage site, or why the furin cleavage site is determined by human-preferred arginine codons instead of by the bat-preferred codons.

Where we are so far. Neither the natural emergence nor the lab escape hypothesis can yet be ruled out. There is still no direct evidence for either. So no definitive conclusion can be reached.

That said, the available evidence leans more strongly in one direction than the other. Readers will form their own opinion. But it seems to me that proponents of lab escape can explain all the available facts about SARS2 considerably more easily than can those who favor natural emergence.

It’s documented that researchers at the Wuhan Institute of Virology were doing gain-of-function experiments designed to make coronaviruses infect human cells and humanized mice. This is exactly the kind of experiment from which a SARS2-like virus could have emerged. The researchers were not vaccinated against the viruses under study, and they were working in the minimal safety conditions of a BSL2 laboratory. So escape of a virus would not be at all surprising. In all of China, the pandemic broke out on the doorstep of the Wuhan institute. The virus was already well adapted to humans, as expected for a virus grown in humanized mice. It possessed an unusual enhancement, a furin cleavage site, which is not possessed by any other known SARS-related beta-coronavirus, and this site included a double arginine codon also unknown among beta-coronaviruses. What more evidence could you want, aside from the presently unobtainable lab records documenting SARS2’s creation?

Proponents of natural emergence have a rather harder story to tell. The plausibility of their case rests on a single surmise, the expected parallel between the emergence of SARS2 and that of SARS1 and MERS. But none of the evidence expected in support of such a parallel history has yet emerged. No one has found the bat population that was the source of SARS2, if indeed it ever infected bats. No intermediate host has presented itself, despite an intensive search by Chinese authorities that included the testing of 80,000 animals. There is no evidence of the virus making multiple independent jumps from its intermediate host to people, as both the SARS1 and MERS viruses did. There is no evidence from hospital surveillance records of the epidemic gathering strength in the population as the virus evolved. There is no explanation of why a natural epidemic should break out in Wuhan and nowhere else. There is no good explanation of how the virus acquired its furin cleavage site, which no other SARS-related beta-coronavirus possesses, nor why the site is composed of human-preferred codons. The natural emergence theory battles a bristling array of implausibilities.

The records of the Wuhan Institute of Virology certainly hold much relevant information. But Chinese authorities seem unlikely to release them given the substantial chance that they incriminate the regime in the creation of the pandemic. Absent the efforts of some courageous Chinese whistle-blower, we may already have at hand just about all of the relevant information we are likely to get for a while.

So it’s worth trying to assess responsibility for the pandemic, at least in a provisional way, because the paramount goal remains to prevent another one. Even those who aren’t persuaded that lab escape is the more likely origin of the SARS2 virus may see reason for concern about the present state of regulation governing gain-of-function research. There are two obvious levels of responsibility: the first, for allowing virologists to perform gain-of-function experiments, offering minimal gain and vast risk; the second, if indeed SARS2 was generated in a lab, for allowing the virus to escape and unleash a world-wide pandemic. Here are the players who seem most likely to deserve blame.

  1. Chinese virologists. First and foremost, Chinese virologists are to blame for performing gain-of-function experiments in mostly BSL2-level safety conditions which were far too lax to contain a virus of unexpected infectiousness like SARS2. If the virus did indeed escape from their lab, they deserve the world’s censure for a foreseeable accident that has already caused the deaths of three  million people. True, Shi was trained by French virologists, worked closely with American virologists and was following international rules for the containment of coronaviruses. But she could and should have made her own assessment of the risks she was running. She and her colleagues bear the responsibility for their actions.

I have been using the Wuhan Institute of Virology as a shorthand for all virological activities in Wuhan. It’s possible that SARS2 was generated in some other Wuhan lab, perhaps in an attempt to make a vaccine that worked against all coronaviruses. But until the role of other Chinese virologists is clarified, Shi is the public face of Chinese work on coronaviruses, and provisionally she and her colleagues will stand first in line for opprobrium.

2. Chinese authorities. China’s central authorities did not generate SARS2, but they sure did their utmost to conceal the nature of the tragedy and China’s responsibility for it. They suppressed all records at the Wuhan Institute of Virology and closed down its virus databases. They released a trickle of information, much of which may have been outright false or designed to misdirect and mislead. They did their best to manipulate the WHO’s inquiry into the virus’s origins, and led the commission’s members on a fruitless run-around. So far they have proved far more interested in deflecting blame than in taking the steps necessary to prevent a second pandemic.

3. The worldwide community of virologists. Virologists around the world are a loose-knit professional community. They write articles in the same journals. They attend the same conferences. They have common interests in seeking funds from governments and in not being overburdened with safety regulations.

Virologists knew better than anyone the dangers of gain-of-function research. But the power to create new viruses, and the research funding obtainable by doing so, was too tempting. They pushed ahead with gain-of-function experiments. They lobbied against the moratorium imposed on Federal funding for gain-of-function research in 2014, and it was raised in 2017.

The benefits of the research in preventing future epidemics have so far been nil, the risks vast. If research on the SARS1 and MERS viruses could only be done at the BSL3 safety level, it was surely illogical to allow any work with novel coronaviruses at the lesser level of BSL2. Whether or not SARS2 escaped from a lab, virologists around the world have been playing with fire.

Their behavior has long alarmed other biologists. In 2014 scientists calling themselves the Cambridge Working Group urged caution on creating new viruses. In prescient words, they specified the risk of creating a SARS2-like virus. “Accident risks with newly created ‘potential pandemic pathogens’ raise grave new concerns,” they wrote. “Laboratory creation of highly transmissible, novel strains of dangerous viruses, especially but not limited to influenza, poses substantially increased risks. An accidental infection in such a setting could trigger outbreaks that would be difficult or impossible to control.”

When molecular biologists discovered a technique for moving genes from one organism to another, they held a public conference at Asilomar in 1975 to discuss the possible risks. Despite much internal opposition, they drew up a list of stringent safety measures that could be relaxed in future — and duly were — when the possible hazards had been better assessed.

When the CRISPR technique for editing genes was invented, biologists convened a joint report by the US, UK and Chinese national academies of science to urge restraint on making heritable changes to the human genome. Biologists who invented gene drives have also been open about the dangers of their work and have sought to involve the public.

You might think the SARS2 pandemic would spur virologists to re-evaluate the benefits of gain-of-function research, even to engage the public in their deliberations. But no. Many virologists deride lab escape as a conspiracy theory, and others say nothing. They have barricaded themselves behind a Chinese wall of silence which so far is working well to allay, or at least postpone, journalists’ curiosity and the public’s wrath. Professions that cannot regulate themselves deserve to get regulated by others, and this would seem to be the future that virologists are choosing for themselves.

4. The US role in funding the Wuhan Institute of Virology. From June 2014 to May 2019, Daszak’s EcoHealth Alliance had a grant from the National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health, to do gain-of-function research with coronaviruses at the Wuhan Institute of Virology. Whether or not SARS2 is the product of that research, it seems a questionable policy to farm out high-risk research to unsafe foreign labs using minimal safety precautions. And if the SARS2 virus did indeed escape from the Wuhan institute, then the NIH will find itself in the terrible position of having funded a disastrous experiment that led to death of more than 3 million worldwide, including more than half a million of its own citizens.

The responsibility of the NIAID and NIH is even more acute because for the first three years of the grant to EcoHealth Alliance, there was a moratorium on funding gain-of-function research. Why didn’t the two agencies therefore halt the federal funding, as apparently required to do so by law? Because someone wrote a loophole into the moratorium.

The moratorium specifically barred funding any gain-of-function research that increased the pathogenicity of the flu, MERS, or SARS viruses. But then a footnote on page 2 of the moratorium document states that “[a]n exception from the research pause may be obtained if the head of the USG funding agency determines that the research is urgently necessary to protect the public health or national security.”

This seems to mean that either the director of the NIAID, Anthony Fauci, or the director of the NIH, Francis Collins, or maybe both, would have invoked the footnote in order to keep the money flowing to Shi’s gain-of-function research.

“Unfortunately, the NIAID director and the NIH director exploited this loophole to issue exemptions to projects subject to the Pause—preposterously asserting the exempted research was ‘urgently necessary to protect public health or national security’ — thereby nullifying the Pause,” Ebright said in an interview with Independent Science News.

When the moratorium was ended in 2017, it didn’t just vanish but was replaced by a reporting system, the Potential Pandemic Pathogens Control and Oversight (P3CO) Framework, which required agencies to report for review any dangerous gain-of-function work they wished to fund.

According to Ebright, both Collins and Fauci “have declined to flag and forward proposals for risk-benefit review, thereby nullifying the P3CO Framework.”

In his view, the two officials, in dealing with the moratorium and the ensuing reporting system, “have systematically thwarted efforts by the White House, the Congress, scientists, and science policy specialists to regulate GoF [gain-of-function] research of concern.”

Possibly the two officials had to take into account matters not evident in the public record, such as issues of national security. Perhaps funding the Wuhan Institute of Virology, which is believed to have ties with Chinese military virologists, provided a window into Chinese biowarfare research. But whatever other considerations may have been involved, the bottom line is that the National Institutes of Health was supporting gain-of-function research, of a kind that could have generated the SARS2 virus, in an unsupervised foreign lab that was doing work in BSL2 biosafety conditions. The prudence of this decision can be questioned, whether or not SARS2 and the death of 3 million people were the result of it, which emphasizes the need for some better system of control.

In conclusion. If the case that SARS2 originated in a lab is so substantial, why isn’t this more widely known? As may now be obvious, there are many people who have reason not to talk about it. The list is led, of course, by the Chinese authorities. But virologists in the United States and Europe have no great interest in igniting a public debate about the gain-of-function experiments that their community has been pursuing for years.

Nor have other scientists stepped forward to raise the issue. Government research funds are distributed on the advice of committees of scientific experts drawn from universities. Anyone who rocks the boat by raising awkward political issues runs the risk that their grant will not be renewed and their research career will be ended. Maybe good behavior is rewarded with the many perks that slosh around the distribution system. And if you thought that Andersen and Daszak might have blotted their reputation for scientific objectivity after their partisan attacks on the lab escape scenario, look at the second and third names on this list of recipients of an $82 million grant announced by the National Institute of Allergy and Infectious Diseases in August 2020.

The US government shares a strange common interest with the Chinese authorities: Neither is keen on drawing attention to the fact that Shi’s coronavirus work was funded by the US National Institutes of Health. One can imagine the behind-the-scenes conversation in which the Chinese government says, “If this research was so dangerous, why did you fund it, and on our territory too?” To which the US side might reply, “Looks like it was you who let it escape. But do we really need to have this discussion in public?”

Fauci is a longtime public servant who served with integrity under President Trump and has resumed leadership in the Biden Administration in handling the COVID-19 epidemic. Congress, no doubt understandably, may have little appetite for hauling him over the coals for the apparent lapse of judgment in funding gain-of-function research in Wuhan.

To these serried walls of silence must be added that of the mainstream media. To my knowledge, no major newspaper or television network has yet provided readers with an in-depth news story of the lab escape scenario, such as the one you have just read, although some have run brief editorials or opinion pieces. One might think that any plausible origin of a virus that has killed three million people would merit a serious investigation. Or that the wisdom of continuing gain-of-function research, regardless of the virus’s origin, would be worth some probing. Or that the funding of gain-of-function research by the NIH and NIAID during a moratorium on such research would bear investigation. What accounts for the media’s apparent lack of curiosity?

The virologists’ omertà is one reason. Science reporters, unlike political reporters, have little innate skepticism of their sources’ motives; most see their role largely as purveying the wisdom of scientists to the unwashed masses. So when their sources won’t help, these journalists are at a loss.

Another reason, perhaps, is the migration of much of the media toward the left of the political spectrum. Because President Trump said the virus had escaped from a Wuhan lab, editors gave the idea little credence. They joined the virologists in regarding lab escape as a dismissible conspiracy theory. During the Trump administration, they had no trouble in rejecting the position of the intelligence services that lab escape could not be ruled out. But when Avril Haines, President Biden’s director of national intelligence, said the same thing, she too was largely ignored. This is not to argue that editors should have endorsed the lab escape scenario, merely that they should have explored the possibility fully and fairly.

People round the world who have been pretty much confined to their homes for the last year might like a better answer than their media are giving them. Perhaps one will emerge in time. After all, the more months pass without the natural emergence theory gaining a shred of supporting evidence, the less plausible it may seem. Perhaps the international community of virologists will come to be seen as a false and self-interested guide. The common sense perception that a pandemic breaking out in Wuhan might have something to do with a Wuhan lab cooking up novel viruses of maximal danger in unsafe conditions could eventually displace the ideological insistence that whatever Trump said can’t be true.

And then let the reckoning begin.

A rare black fungus is infecting many of India’s COVID-19 patients—why?

(Update 5/30/2021)

Indiscriminate steroid usage and high blood sugar levels are potentially responsible for driving an uptick in a rare fungal infection among vulnerable COVID-19 patients.

On May 9, Ananyaa Mazumdar received a call that left her stumped. Her panic-stricken cousin explained that her 48-year-old aunt, who had recently recovered from a COVID-19 infection, had lost most of her vision in both eyes.

The emergency room doctors at the Max Super Speciality Hospital in Ghaziabad, a satellite city outside India’s capital New Delhi, suggested that because the infection was so advanced, she needed immediate surgery to remove her eyes. Aghast at first, the family soon realized that they had no other option.

“It’s all that could be done—and had to be done,” Mazumdar said. “It’s like we were sitting on a ticking time bomb.”

Her diabetic aunt was diagnosed with an extremely rare fungal infection called mucormycosis that’s on the rise among recovering and recovered-but-vulnerable COVID-19 patients in India. Colloquially referred to as “black fungus” due to its dark pigmentation, this potentially fatal infection starts in the nose and spreads to the eyes and then the brain.

Public health experts are blaming the indiscriminate use of steroids to treat COVID-19 as the likely cause. Steroids reduce inflammation in the lungs. But overuse of these drugs in COVID-19 patients can result in lowered immunity and raised blood sugar levels. These conditions leave some patients, particularly those with uncontrolled diabetes, susceptible to such infections.

As India—the diabetes capital of the world—continues to battle a devastating second wave of COVID-19, ear, nose and throat physicians are expecting to see more mucormycosis cases come their way in the next few weeks.

In Delhi, for instance, Manish Munjal, an ENT surgeon at Sir Ganga Ram Hospital, has been treating nearly 15 new cases every day since last week. According to him, the city has recorded about 250 mucormycosis cases since April.

“That’s a huge number,” he says, comparing it to a case or two he’d treat every month in pre-pandemic times.

In the western Indian state of Maharashtra, which has been hit hardest by COVID-19, state health minister Rajesh Tope said there could be more than 2,000 mucormycosis patients. In the neighboring state of Gujarat, some 300 cases have been reported from four cities.

“The concern is that this is just the start,” Munjal says. “The infection typically begins to hit the body two to three weeks into the steroid therapy, and we might see the case numbers jump in the coming weeks.”

What is the black fungus?

Mucormycosis is an invasive infection caused by a class of molds called mucormycetes. These fungi are ubiquitous, naturally occurring in our environment, most commonly in soil. Humans get the infection by inhaling the fungal spores floating around in the air and in dust. These spores get lodged in the nasal passages and sinuses and cause disease at that site.

But not everyone exposed to the spores will get the infection. “For most part, if you have a normal immune system, it’s an asymptomatic, silent encounter,” says Tobias Hohl, chief of infectious disease service at New York’s Memorial Sloan Kettering Cancer Center. But developing the invasive disease depends on a person’s health condition.

People with compromised immune systems, for example, those with blood cancer undergoing chemotherapy or bone-marrow transplant patients who can’t form neutrophils—a type of white blood cell that defends against infections—in the initial weeks, may fall victim to mucormycosis.

Similarly, during COVID-19, patients prescribed heavy and prolonged steroid doses can have weakened immune systems. “We’ve seen people go crazy with steroid prescriptions,” says Lancelot Pinto, a pulmonologist at Mumbai’s P.D. Hinduja Hospital and Medical Research Center. “There’s a misperception among doctors that more severe the [COVID-19] case, higher the dose of steroids needed, which isn’t supported by any trial so far.”

Steroids can cause blood sugar levels to spike, which can be especially challenging for patients with uncontrolled diabetes. Higher blood sugar levels and more acidic blood creates a fertile environment for Mucorales fungi to thrive.

In such vulnerable patients, the spores germinate to form long tubular filaments that can grow into the sinuses, into the bone, and the blood stream. The symptoms of mucormycosis and progression of the infection can vary from person to person; they include a throbbing headache, fever, facial and nasal pain, blackish nasal discharge, loss of vision, toothache, loosening of teeth, swelling in the upper jaw, and sometimes face paralysis.

“This is a horrific infection, and can be disfiguring,” Hohl says. “Unless treated, the infection can cross into the central nervous system, and that’s more dangerous.” The chances of dying exceeds 50 percent if the infection reaches the brain.

Early diagnosis can be lifesaving. But the infections can be extremely challenging to treat, even at an early stage.

Treating mucormycosis

Patients are prescribed antifungal treatments such as liposomal amphotericin B injections for at least 10 days to several weeks after diagnosis. But these essential drugs have the potential to induce substantial side-effects, including kidney damage.

Often, a surgical intervention is also needed. In less severe cases doctors insert an endoscope through the nasal cavity and remove any diseased tissue. If the infection has spread further, the surgeons may need to remove the eyes or the jaw bone.

At the Samadhan Dental Super Specialty Center in Dhule, Maharashtra, oral and maxillofacial surgeons Rajesh and Shrenik Oswal have since April treated nearly 50 former COVID-19 patients with mucormycosis of the jaw, 25 of whom have had their jaw fully or partially removed to stop the disease spread.

Ajinkya Kelkar, an ENT surgeon in Pune city’s Maharashtra Medical Foundation Hospitals, has recently treated a dozen COVID-19-associated mucormycosis patients, two of whom underwent complete eye removal. Pre-pandemic, he would encounter two to three mucormycosis cases every year.

“It’s a serious rise,” he says. “We never expected it.” On Sunday, the Indian Council of Medical Research issued an advisory for the screening, management and diagnosis of mucormycosis in the time of COVID-19.

For now, though, these unexpected infections have brought new challenges for patients who are already physically, emotionally, and financially depleted from a recent COVID-19 infection.

The surging demand for antifungal medication has created an acute shortage, giving rise to a back market for drugs that were already too expensive for most people to afford. In an overwhelmed healthcare system, finding hospitals where mucormycosis patients can get surgery and post-operative care can be another logistical nightmare.

While India’s mucormycosis cases surface in only a small fraction of the country’s total COVID-19 case numbers, the uptick is concerning. To prevent such infections in the first place, public health experts stress that hospitals maintain hygiene, especially for equipment that dispenses oxygen. They advise that doctors prescribe steroids judiciously and suggest regular monitoring of blood sugar levels for all COVID-19 patients in the hospital and at home, even in the post-recovery period.

What you need to know about the COVID-19 lab-leak hypothesis

(Update 6/4/2021)

Newly reported information has revived scrutiny of this possible origin for the coronavirus, which experts still call unlikely though worth investigating.

Months after a World Health Organization investigation deemed it “extremely unlikely” that the novel coronavirus escaped accidentally from a laboratory in Wuhan, China, the idea is back in the news, giving new momentum to a hypothesis that many scientists believe is unlikely, and some have dismissed as a conspiracy theory.

The renewed attention comes on the heels of President Joe Biden’s ordering U.S. intelligence agencies on May 26 to “redouble their efforts” to investigate the origins of the coronavirus. On May 11, Biden’s chief medical adviser, Anthony Fauci, acknowledged he’s now “not convinced” the virus developed naturally—an apparent pivot from what he told National Geographic in an interview last year. 

Also last month, more than a dozen scientists—top epidemiologists, immunologists, and biologists—wrote a letter published in the journal Science calling for a thorough investigation into two viable origin stories: natural spillover from animal to human, or an accident in which a wild laboratory sample containing SARS-CoV-2 was accidentally released. They urged that both hypotheses “be taken seriously until we have sufficient data,” writing that a proper investigation would be “transparent, objective, data-driven, inclusive of broad expertise, subject to independent oversight,” with conflicts of interest minimized, if possible.

“Anytime there is an infectious disease outbreak it is important to investigate its origin,” says Amesh Adalja, an infectious disease physician and senior scholar at the Johns Hopkins University Center for Health Security who did not contribute to the letter in Science. “The lab-leak hypothesis is possible—as is an animal spillover,” he says, “and I think that a thorough, independent investigation of its origins should be conducted.”

Unanswered questions

The origins of SARS-CoV-2, the virus that causes COVID-19 and has infected more than 171 million people, killing close to 3.7 million worldwide as of June 4, remain unclear. Many scientists, including those that participated in the WHO’s months-long investigation, believe the most likely explanation is that that it jumped from an animal to a person—potentially from a bat directly to a human, or through an intermediate host. Animal-to-human transmission is a common route for many viruses; at least two other coronaviruses, SARS and MERS, were spread through such zoonotic spillover.

Other scientists insist it’s worth investigating whether SARS-CoV-2 escaped from the Wuhan Institute of Virology, a laboratory that has studied coronaviruses in bats for more than a decade.

The WHO investigation—a joint effort between WHO-appointed scientists and Chinese officials—concluded it was “extremely unlikely” the highly transmissible virus escaped from a laboratory. But the WHO team suffered roadblocks that led some to question its conclusions; the scientists were not permitted to conduct an independent investigation and were denied access to any raw data. (We still don’t know the origins of the coronavirus. Here are 4 scenarios.)

On March 30, when the WHO released its report, its director-general, Tedros Adhanom Ghebreyesus, called for further studies. “All hypotheses remain on the table,” he said at the time.

Then on May 11, Fauci told PolitiFact that while the virus most likely emerged via animal-to-human transmission, “it could have been something else, and we need to find that out.”

Recently disclosed evidence, first reported by the Wall Street Journal, has added fuel to the fire: Three researchers from the Wuhan Institute of Virology fell sick in November 2019 and sought hospital care, according to a U.S. intelligence report. In the final days of the Trump administration, the State Department released a statement that researchers at the institute had become ill with “symptoms consistent with both COVID-19 and common seasonal illness.”

Most epidemiologists and virologists who have studied the novel coronavirus believe that it began spreading in November 2019. China says the first confirmed case was on December 8, 2019. During a briefing in Beijing this week, China’s foreign ministry spokesperson, Zhao Lijian, accused the U.S. of “hyping up the theory of a lab leak,” and asked, “does it really care about the study of origin tracing, or is it trying to divert attention?” Zhao also denied the Wall Street Journalreport that three people had gotten sick.

Lab leak still ‘unlikely’

Some conservative politicians and commentators have embraced the lab-leak theory, while liberals more readily rejected it, especially early in the pandemic. The speculation has also heightened ongoing tensions between the U.S. and China.

On May 26, as the U.S. Senate passed a bill to declassify intelligence related to potential links between the Wuhan laboratory and COVID-19, Missouri Senator Josh Hawley, a Republican who sponsored the bill, said, “the world needs to know if this pandemic was the product of negligence at the Wuhan lab,” and lamented that “for over a year, anyone asking questions about the Wuhan Institute of Virology has been branded as a conspiracy theorist.”

Peter Navarro, Donald Trump’s former trade adviser, asserted in April 2020 that SARS-CoV-2 could have been engineered as a bioweapon, without citing any evidence.

The theory that SARS-CoV-2 was created as a bioweapon is “completely unlikely,” says William Schaffner, a professor of infectious diseases at Vanderbilt University Medical Center. For one thing, he explains, for a bioweapon to be successful, it must target an adversarial population without affecting one’s own. In contrast, SARS-CoV-2 “cannot be controlled,” he says. “It will spread, including back on your own population,” making it an extremely “counterproductive biowarfare agent.”

The more plausible lab-leak hypothesis, scientists say, is that the Wuhan laboratory isolated the novel coronavirus from an animal and was studying it when it accidentally escaped. “Not knowing the extent of its virulence and transmissibility, a lack of protective measures [could have] resulted in laboratory workers becoming infected,” initiating the transmission chain that ultimately resulted in the pandemic, says Rossi Hassad, an epidemiologist at Mercy College.

But Hassad adds he believes that this lab-leak theory is on the “extreme low end” of possibilities, and it “will quite likely remain only theoretical following any proper scientific investigation,” he says.

Biden ordered U.S. intelligence agencies to report back with their findings in 90 days, which would be August 26.

Based on the available information, Eyal Oren, an epidemiologist at San Diego State University, says it’s apparent why the most accepted hypothesis is that this virus originated in an animal and jumped to a human: “What is clear is that the genetic sequence of the COVID-19 virus is similar to other coronaviruses found in bats,” he says.

Some scientists remain skeptical that concrete conclusions can be drawn. “At the end, I anticipate that the question” of SARS-CoV-2’s origins “will remain unresolved,” Schaffner says.

In the meantime, science “moves much more slowly than the media and news cycles,” Oren says.

The Delta variant is spreading fast, especially where vaccination rates are low

A new report stresses that only a complete dose of the COVID-19 vaccine can protect against this dangerous variant, which is now dominant in the U.S., U.K., and more than a dozen other countries.

(Updated 7/13/2021)

With just 48 percent of the U.S. population fully vaccinated, and other countries struggling to secure vaccines, public health experts are concerned that the Delta variant—the most dangerous and transmissible form of the coronavirus to date—will trigger dramatic surges in cases and deaths in the U.S. and around the world.

First identified in India in March, Delta is now the dominant variant in the U.S. and accounts for more than half of new infections, according to the latest data from the Centers for Disease Control and Prevention. It has spread to more than 90 countries and is also the most dominant variant in India, the United Kingdom, Russia, Israel, Singapore, and more than a dozen others.

The Delta variant is 60 percent more transmissible than the Alpha variant—first identified in the U.K.—which in turn was about 50 percent more transmissible than the ancestral Wuhan strain. “It’s a super spreader variant; that is worrisome,” says Eric Topol, founder and director of the Scripps Research Translational Institute in California.

Delta has features that allow it to evade some of the body’s immune system defenses, says Topol. “Plus, it has the highest transmissibility of anything we’ve seen so far. It’s a very bad combination.”

In the U.S., Delta is responsible for more than 50 percent of new COVID-19 cases, up from 26 percent the week ending June 19. In parts of the Midwest and the Mountain States, where vaccination rates are lower, genetic analyses of virus samples suggest Delta could account for more than 80 percent of cases, said CDC director Rochelle Walensky during a press briefing on Thursday. She also presented data showing that less than 40 percent of residents were vaccinated in the roughly 170 U.S. counties with the highest case rates. Data from the past few months suggest that 99.5 percent of people who died from COVID-19 in the U.S. were unvaccinated. “So deaths were preventable with a simple, safe shot,” Walensky added.

Indeed, data show that a complete dose of a COVID-19 vaccine is still effective at preventing serious illness from Delta infection. A study published yesterday in the New England Journal of Medicine showed that both the Moderna and Pfizer-BioNTech mRNA vaccines will likely protect against Delta, though not as well as they did with previous variants.

A separate study estimated that two doses of the AstraZeneca or Pfizer vaccines will be be 60 and 88 percent effective, respectively, against symptomatic disease caused by Delta. And there is direct and indirect evidence that the single-shot vaccine from Johnson and Johnson is effective against the Delta variant, according to Anthony Fauci, director of the National Institute of Allergy and Infectious Diseases.

However, a single dose of either mRNA vaccine, or a previous natural infection, barely inhibited the Delta variant, write the authors of another study published yesterday in the journal Nature.

Alarmed by the reduced efficacy against Delta, Pfizer is planning to ask for FDA authorization for a booster dose of its vaccine within the next month. Pfizer and BioNTech also announced on Thursday that they had developed an updated version of their COVID-19 vaccine that would specifically target the Delta variant. The companies expect to begin clinical trials in August.

“The only conclusion one can reasonably come to … is please, get vaccinated. It will protect you against the surging of the Delta variant,” Fauci said at a press conference on Thursday.

Why is the Delta variant so scary?

Freely circulating viruses, especially coronaviruses and influenza viruses, which encode their genetic instructions using the molecule RNA, mutate frequently and randomly due to copying errors introduced as they replicate in their human host cells. Some mutations enable the virus to evade antibodies; some enhance its ability to infect a cell; others go unnoticed since they yield no benefits or can even weaken it.

The key to Delta’s success is the collection of mutations the variant has accumulated in the spike protein, which covers SARS-CoV-2 and gives the virus its signature crown-like appearance. These mutations have changed the spike, and, as a result, some of the existing antibodies may not bind as tightly or as often, explains Markus Hoffmann, an infectious disease biologist at the Leibniz Institute for Primate Research in Germany. Some synthetic antibody therapies, like Bamlanivimab, were unable to neutralize the Delta variant; but others such as Etesivimab, Casirivimab, and Imdevimab were still effective.

The Delta variant has mutations on the spike protein that alter how it interacts with the ACE2 receptor protein, which is found on the surface of lung and other human cells and is the portal to invade the cell. The mutation at location 452 of the spike protein, which is also present in some of the California variants, appears to make the virus moretransmissible and helps it spread through the population, explains Mehul Suthar, an immunologist at the Emory Vaccine Center.

If a mutation gives a virus a fitness or reproductive advantage, that mutation tends to evolve independently around the world. Delta, its closely related variants, and the highly contagious Alpha variant all carry a mutation at position 681 of the spike protein, which is thought to be an evolutionary game changer that also makes it easier for SARS-CoV-2 to invade the host cell and spread. This mutation is fast becoming common in COVID-19 viruses around the globe.

In addition to these mutations a recent study, not peer reviewed, shows a variation at position 478 on Delta’s spike that enables the virus to escape from weak neutralizing antibodies. This mutation has also become increasingly common in SARS-CoV-2 variants in the U.S., Mexico, and Europe since early 2021.

“When you have all of these mutations, then you start seeing a difference in infectivity (of the virus),” says Ravindra Gupta, a professor of clinical microbiology at the University of Cambridge, who has shown in an unpublished studyhow these variants can have a greater potential to cause disease.

Vaccines less effective against this super spreader

The data from India and the U.K. show that Delta emerged as the dominant variant in those countries within four to six weeks. That indicates Delta is more transmissible and infectious than the previous variants. There is emerging evidence that it can also cause more severe disease. For example, in Scotland it caused about twice as many hospitalizations than the Alpha variant, which already caused more severe illness than the original SARS-CoV-2.

“This combination of high transmissibility, high severity, and escape from vaccines makes Delta a very, very dangerous variant,” says Deepti Gurdasani, a clinical epidemiologist at Queen Mary University of London. Once Delta enters a country, it is going to spread rapidly. “It’s going to be quite hard to contain, and very likely will become the dominant variant in a matter of weeks. It could change the trajectory of the global pandemic.”

While vaccines are still effective against severe disease and hospitalization caused by the Alpha and Beta variants, they offer less protection against Delta. People who were vaccinated with one or two doses of the Pfizer vaccine produced lower levels of antibodies capable of neutralizing the Delta variant compared with the levels generated against Alpha and Beta. In the U.K., 31 percent of all confirmed Delta variant patients who needed emergency care had received at least one vaccine dose.

Similarly, a study under review revealed that after both doses, the Pfizer vaccine showed 88 percent effectiveness against symptomatic disease caused by the Delta variant compared to 93 percent against the Alpha variant. Two doses of AstraZeneca vaccine were 66 percent effective against Alpha but only 60 percent against Delta. But with just single dose of either of the two vaccines, the vaccine effectiveness was only 51 percent against the Alpha variant compared to 33 percent against Delta. This effectiveness falls below the 50 percent efficacy threshold the FDA had set for designing safe COVID-19 vaccines; in which a vaccine should prevent at least half of the vaccinated people from getting COVID-19 symptoms.

In other studies still awaiting peer review, researchers report that Delta was responsible for most breakthrough infections—which occur after full vaccination—in India leading to a cluster of such cases among fully vaccinatedhealthcare workers.

There are many vaccine candidates being rolled out around the world and since there are no agreed international efficacy standards, each vaccine might offer a varying degree of protection against new variants. “We need more information about the performance of some of the more widely available vaccines in other parts of the world,” says physician and virologist Benjamin Pinsky of Stanford University School of Medicine. “I think folks need to make sure they get vaccinated. And until they are fully vaccinated, continuing with public health intervention is very important,” he says.

A vaccine alone only slows down the progression of a contagious disease by increasing the herd immunity. Until that point, preventive measures such as social distancing and masking are proven strategies for curbing the spread of the virus.

With just 44 percent of the U.S. population fully vaccinated, the majority of people are still vulnerable. Relaxing public health restrictions and declaring victory prematurely could provide an opportunity for the Delta variant to surge–particularly in the fall.

A study, not yet published, suggests the possibility of seasonal variations in COVID-19 incidence based on analyses from a full year of the pandemic in Europe and Israel. While the virus’s seasonal trends may not be clear yet, says Topol, we do know that when people spend more time indoors with poor ventilation and low humidity the virus spreads more rapidly.

What is happening in the U.K. could occur in many places worldwide. “We should keep social distancing after vaccination, because there will always be possibilities of breakthrough infection because vaccines can still be imperfect against emerging variants,” says Kei Sato,a virologist at the University of Tokyo, Japan, who has been studying the effect of mutations on the transmission of Delta and other emerging variants.

“The more variants like this spread, especially in unvaccinated individuals, the more these viruses mutate and eventually pick up mutations that allow for more efficient antibody escape. This could, in theory, make the current vaccines even less effective against these variants.” Suthar cautions.

If we don’t take Delta seriously, “there will be a further wave in the U.S. We can already see the fall in cases has plateaued,” cautions Gupta. Topol agrees that if we ignore this variant “we’ll have a significant rise in cases in vulnerable areas, more hospitalization, and the pandemic here will last longer.”

Long Covid Has Over 200 Symptoms And Leaves 1 In 5 Unable To Work, Study Finds

(Updated 7/15/2021)

There are more than 200 symptoms associated with long Covid spanning 10 organ systems—including memory loss, hallucinations, tremors and fatigue—according to a new study published Thursday, providing one of the most comprehensive insights yet into the lingering and debilitating illness that can affect patients for months or years after infection. 


Covid long haulers reported a total of 203 different symptoms in the seven months between Dec. 2019 and May 2020, ranging from rashes, peeling skin and digestive issues to muscle spasms, hearing loss and tinnitus, according to research published in the Lancet’s E Clinical Medicine journal.

The study, based on surveys from nearly 4,000 people from 56 countries, identified fatigue, brain fog and post-exertional malaise (where symptoms worsen after physical or mental effort) as the most common symptoms.

On average, patients suffered from 56 different symptoms and those still suffering after six months—nearly two-thirds of participants taking the survey—were still experiencing an average of 14 symptoms.

Almost half (45%) of the study’s participants reported needing a reduced work schedule on account of their illness and around one-fifth (22%) were unable to work at all.  

Dr. Athena Akrami, a neuroscientist at University College London and senior author of the study, said it highlights “a clear need to widen medical guidelines” to assess a wider range of symptoms than respiratory and cardiovascular issues for long Covid.”


The researchers noted that patients reported experiencing symptoms that are “not commonly mentioned in public discussion of long Covid,” like seizures, suicidality, facial paralysis, new allergies and changes in sensitivities to medication. 


The findings reinforce the understanding that Covid-19 is far more than a respiratory illness and has an effect on the entire body. It also highlights that some symptoms may only emerge after months or weeks of the initial infection. Severity of the initial infection does not appear to be strongly linked to the chances of getting long Covid, making children and young people—along with the unvaccinated—especially vulnerable. Given that the majority of early research only covered hospitalized patients and the continued lack of consistent diagnostic criteria, it’s not yet known how common long Covid might be. Studies suggest around 10% to 30% of Covid-19 patients may go on to become these “long haulers,” though this figure is likely to change as more research is conducted. 


There’s also no sense yet of the duration of long Covid. The researchers estimated more than 90% of the cohort studied to still experience symptoms after six months. Other post-infection syndromes can vary from weeks to decades in duration, some only manifesting long after the initial infection is cleared. Dr. David Strain, a senior clinical lecturer at the University of Exeter, told Forbes the nearest illness to long Covid is probably chronic fatigue syndrome (also known as ME), which can last decades.


33.9 million. That’s how many people in the U.S. have had Covid-19, according to data from Johns Hopkins University. Using a conservative estimate of 10% for how many people go on to develop long Covid and subtracting how many have died from Covid-19, that’s 3.3 million Americans who could be living with persistent, debilitating symptoms. 

The unusual Lambda variant is rapidly spreading in South America. Here’s what we know.

(Update 7/25/2021)

Its mutations help it dodge the immune system. Researchers are scrambling to figure out if it is more dangerous or transmissible than Delta.

A coronavirus variant known as Lambda, which has largely slid under the radar for the past nine months, is now causing almost all new infections in Peru.

Lambda (also known as C.37) was first detected in Peru in August 2020 and has spread to 29 countries, many in Latin America. And, since January 20, 2021, 668 Lambda infections have been reported in the United States. In Peru, Lambda is now responsible for more than 90 percent of new COVID-19 cases, a steep rise from less than 0.5 percent in December. The country has already suffered the world’s worst mortality due to COVID-19; the disease has killed about 0.54 percent of the population.

The Lambda variant likely caused the high number of infections during the second wave between the end of March and April, Peruvian Minister of Health Óscar Ugarte said in a news conference. In neighboring Chile, where the primary vaccine is China’s CoronaVac, Lambda accounts for 31 percent of sequenced cases in the last 60 days. The high case numbers are occurring even though 58.6 percent of Chile’s population is fully vaccinated and another 10 percent has received a single dose. The poor efficacy of the vaccine maybe partly to blame. A study by the University of Chile found that a single dose of the CoronaVac vaccine was only 3 percent effective, but that rose to 56.5 percent after both doses.

“Why Chile is getting such high infection rates is perplexing, and it’s likely due to several factors. Because of their high vaccination coverage, the restrictions were relaxed a little too soon, and that could have led to [a] rise in cases,” says Pablo Tsukayama, a microbiologist at Universidad Peruana Cayetano Heredia in Lima, Peru. It was Tsukayama who first spotted the Lambda variant after routinely sequencing the samples deposited between January and March 2021. “But it is also possible that the main variants in circulation, Gamma and Lambda, have some immune escape properties that lead to reduced protection from vaccines.”

The possibility that Lambda might be able to dodge the immune system led the World Health Organization to designate it as a Variant of Interest (VOI) on June 14. WHO categorizes a virus as a VOI when genetic changes in the virus are so significant that they may affect its transmissibility, disease severity, immune escape, diagnosis or therapy; and it spreads rapidly through a community.

While Latin America has only eight percent of the world’s population, it makes up more than 20 percent of global coronavirus cases and 32 percent of COVID-19 deaths worldwide. Although the region is still reporting more than half of the deaths registered globally, only one in 10 Latin Americans have been fully vaccinated. In countries such as Honduras and Guatemala, the number is less than 1 percent.

“I think we are about to see another critical situation in the next few weeks in Latin America,” says Alfonso Rodriguez-Morales, an epidemiologist and vice president of the Colombian Association of Infectious Diseases. That is because in some countries the vaccination programs still have not fully vaccinated more than 5 to 10 percent of their populations “and that is very critical.”

Why it is hard to detect variants? 

The Lambda variant remained undetected for many months because it was frequently mistaken for Gamma—the variant first identified in Brazil and also known as P.1.

Due to limited resources, the Peruvian National Institute of Health uses a fast and affordable method  based on the changes in the virus’s ORF1ab gene. That method cannot distinguish Beta and Gamma variants from Lambda. To sort the Lambda variant from others requires genetic sequencing, a costly and time-consuming process.

“We have very limited capacity in the region to conduct genomics surveillance, so estimating full prevalence of Lambda is difficult. Why any variant becomes dominant is not easy to predict. So, it is important that we ramp sequencing capacity in all places, not just in the United States and Europe,” says Tsukayama.

What has changed in Lambda?

The Lambda variant is very unusual because of the way its spike protein is altered compared to other variants. It has mutations at 14 positions including a long stretch of seven amino acids which has been deleted from a region of the spike protein called the N-terminal domain or NTD. Beyond these, Lambda also has mutations in the ORF1abgene that are found in other variants of concern: Alpha, Beta, and Gamma.

The ORF1ab gene encodes a large protein, parts of which help the coronavirus replicate and suppress the human immune response. Because of its importance, scientists are already developing antiviral therapies to target ORF1ab proteins.

The seven amino acids deleted from the NTD belong to an NTD supersite where the spike is attacked by many of the body’s potent antibodies. Many variants, including Alpha, Beta, and Gamma also harbor mutations within this zone, suggesting that this region is important for the evolution of the virus. “NTD is not crucial for carrying out important functions of the virus and thus, it is easy for the virus to mutate and still remain viable, so as to evade the existing antibody response,” explains Shee-Mei Lok, an infectious disease scientist at National University of Singapore.

The anti-NTD antibodies made naturally in the body may block subsequent viruses from entering the cell even after it has attached with the ACE2 receptor on the cell’s surface, which is why vaccine developers are focusing on it.

Among other mutations of Lambda is a unique one at location 452 which is also mutated in other highly transmissive variants: Delta, Delta Plus, Epsilon, and Kappa. While Lambda’s L452Q mutation has never been seen before in a variant, scientists predict that mutations at the 452 position boost the ability of SARS-CoV-2 to infect a cell.

The 452 position occurs in the part of the spike protein that interacts directly with the ACE2 receptor protein found on the lung and other human cells, and that interaction allows it to enter the body. “The 452 position is recognized by many neutralizing antibodies. Mutations at this site could result in decreased binding and thus less protection by certain vaccines in certain people, those with marginal responses to start with,” says Michael Diamond, an immunologist at Washington University School of Medicine.

Evgeni Sokurenko, a microbiologist at University of Washington, has shown that a single mutation at this position could have set off the recent rapid expansion of COVID-19 variants. A similar mutation—L452R—in the Epsilon variant causes high infectiousness, enhances the virus’s capacity to grow, and reduces the neutralizing activity of many antibodies.

In a study not yet peer reviewed, Nathaniel Landau, a microbiologist at the NYU Grossman School of Medicine, has shown that a lab-made Lambda-like virus was twice as infectious as the early SARS-CoV-2 variant, due only to the L452Q. Other mutations found in Lambda had no significant effect on infectivity. Another study not yet peer reviewed also confirms that Lambda is likely more infectious than Gamma and Alpha.

What do we know about vaccines and Lambda?

There are very few studies on Lambda, but preliminary results suggest that current vaccines are still effective but perhaps less than against the original virus.

“We believe that, at least for the mRNA vaccines—Moderna and Pfizer, that those vaccines will protect very well against Lambda, in the same way that they protect against the Delta virus. Even though some of the antibody no longer works against the variants, it’s still enough that they will fight the virus and get rid of it pretty well,” assures Landau who led one study.

Another study, also not yet peer reviewed, shows that Lambda can escape the neutralizing antibodies produced by the WHO approved, China-developed CoronaVac vaccine, although lead author Ricardo Soto Rifo, a virologist at the Institute of Biomedical Sciences, Santiago, Chile, clarified, “We still don’t have evidence to say that Lambda is more transmissible, we don’t have evidence to say that Lambda is responsible for vaccine breakthrough, we don’t have evidence to state that Lambda is responsible for more severe disease or whether Lambda is responsible for death.”

Two doses of CoronaVac, an inactivated virus vaccine which is the available vaccine in many Latin American countries, is considered less effective than the mRNA vaccines, but is still good in protecting against severe disease and death.

Despite some skepticism around the efficacy of CoronaVac against new variants, everyone should get vaccinated by whatever authorized vaccine is available in their region, says Herbert Virgin, an immunologist, a member of the National Academy of Sciences, and chief scientific officer of Vir Biotechnology. “If you don’t vaccinate … the virus will evolve,” adds Virgin.

Although worrying about a new variant like Lambda gaining ground in a faraway country might seem excessive, it is important to stay vigilant and follow precautionary measures. “Lambda isn’t scarier than the Delta virus. The key is, that they’re both highly transmissible viruses. But if you get the vaccine, you’re most likely going to be protected,” Landau advises. “And the rate of infection with these viruses is going to go down in areas where people get the vaccine.”


(Updated 7/13/2021)

SHAPIRO: Debunking Biden’s COVID Lies

By Ben Shapiro

So you keep hearing that Joe Biden is doing a magnificent job on COVID. That he inherited a mess, and now we’re on the right track. 

Here’s the problem: That’s not true. They’re not following the science. They’re lying about the plans. They’re setting unattainable standards for reopening.

And they are doing all of this for political gain.

Throughout this pandemic, the media particularly have been in the bag for the Democrats. The media routinely said that Donald Trump was lying when he said that within the year there would be a vaccine. 

Here’s the thing: he was right. 

In fact, they only announced the efficacy of the vaccine one week after the election. I don’t think that’s a coincidence, actually.

The vaccines had already been developed. The U.S. government was always going to buy these vaccines. It is states that have been tranching out the vaccines.

By the end of February, here is how many sites Joe Biden’s administration had set up: seven.

According to Bloomberg News, his administration’s distribution of vaccines so far looks little different from that of its predecessor.

Biden and White House Press Secretary Jen Psaki said repeatedly that their goal was 100 million shots in 100 days. 

Well, here’s the thing: America was already injecting a million people per day by the time Biden took office.

In reality, here’s what the Biden administration did: they got elected. That’s the whole thing.

The media kept claiming over and over and over that on the eve of the pandemic, Trump cut the CDC budget.

That’s not true, even according to Trump may have proposed cuts; the cuts never happened. In fact, the CDC budget increased. By the way, citing people’s budgetary proposals is actually the basis for failure. It is itself a fail. Budgetary proposals never make it into law.

Then there’s the claim Trump said coronavirus was a hoax. 

He never said that coronavirus was a hoax. Trump instead said that the way that the media was treating him over coronavirus was a hoax. That’s what he actually said. 

And by the way, he was right about hydroxychloroquine being a treatment that has now been authorized for emergency use.

The insane hatred for hydroxychloroquine just because Trump mentioned the drug? It was indeed a crazy thing.

One of the areas where the Trump administration should have done better was in ramping up testing very early. But the reality is that as the pandemic progressed, testing was not chiefly the issue because once we had moved into community spread phase, there was no way to do testing and tracing. It just was not possible once you had tens of thousands of cases — hundreds of thousands of cases — simultaneously across the United States. 

At that point, we were not going to test our way out of the pandemic. The only solution was a vaccine.

There’s no question: the Biden administration is more pro-mask than the Trump administration. But we are now a year into the pandemic and masking is no longer the chief issue. Yet, that still seems to be the thing that Biden talks about the most, which suggests that a lot of this is about optics, not about efficacy.

Trump was right about schools. He said early on that schools should be opened. He was consistently right about that. Democrats are still insisting that many schools should not be open. 

Now, CDC Director Rochelle Walensky has pointed out that schools could open safely without teachers being vaccinated.

One of the most robust findings in science is that schools — particularly for elementary school students — do not increase risks to teachers. In fact, studies show that the baseline level of risk to teachers is no different from the baseline level that all adults in a society experience from COVID.

But the White House didn’t like that because it suggested that schools should be open. Teachers unions don’t want the schools open.

According to Joe Biden, “reopening schools safely will be a national priority for the Biden-Harris administration. They need to open safely under the circumstances.” That sentiment was echoed by White House Press Secretary Jen Psaki, who said “We can reopen them… but we want to do it safely.”

“Safely” can mean literally anything because you can always say that schools are just not safe enough.

Here’s the thing. Well over half of schools are already open.

The Biden administration — which is a lockdown administration — is doing this entirely in contravention of the available data.

Florida and California took precisely the opposite tacts. California shut down forever; Florida stopped the shutdown in the middle of last summer. They have a very similar death per million rate. The only difference is that Florida is the second oldest state in America; California is the fifth youngest state in America. California wrecked its economy, wrecked its freedom, wrecked everything. 

Dr. Anthony Fauci says we can never go back to normal until there is no risk. 

There is no such thing as no risk. There will always be risk when it comes to COVID, so long as COVID is with us. 

The actual disappearance of the disease is not likely. So the question is risk assessment. The Biden administration does not want to do risk assessment. Instead, it would like to prolong the feeling of crisis.

Deaths are down precipitously. Cases are down precipitously. Vaccinations are up precipitously. And yet we keep hearing that we’re still in crisis mode — “maybe we’ll get back to normal next year.” The truth is there’s been an entire cottage industry dedicated to the idea that COVID should make you afraid for your life at all times. 

The reality is that we have been living with this virus for a year. Many Americans have been going out, have been going to work. Many Americans who are younger have been participating in everyday life. Many Americans have already gotten COVID and recovered from it because the death rates on COVID are not 10%. They’re not 5%. The death rates on COVID — for the bulk of the American population overall — total 5 in 1000. 

Why are they doing all this? Because they have an agenda. They want to spend $1.9 trillion in COVID relief. 

By the way: that $1.9 trillion in COVID relief? That includes hundreds of billions of dollars for state and local bailouts. A huge majority of states didn’t even lose tax revenue during 2020 because of the bailouts we already did, but Biden wants to bail out those states anyway. Which states does he want to bail out? The blue states, of course, because those are the states that have systemic debt problems.

The actual financial shortfall this year from COVID is gonna be about $450 billion in terms of GDP. So he’s gonna spend $1.9 trillion, which is crazy. 

All of this is just a political agenda.

(Updated 7/25/2021)

Delta variant prompts venues to rethink how we stand in line

Can new technology, old-fashioned manners, and floor stickers make the waiting game simpler and safer?

A year-and-a-half into the COVID-19 pandemic, few Americans are being mindful about how they stand in line. At airports, theme parks, highway rest stops, and fast-food joints, there have only been small changes in the thinking about queuing up.

But as the Delta variant—and renewed mask mandates—sweep across the country and world, is it time for airports, restaurants, and other attractions to reconsider the conventional wisdom about lines’ efficiency and safety? In an era when commerce and countries have been forced to whipsaw between being shuttered or open, businesses, social scientists, and travelers are contending with fresh policies (and some old issues) about how to wait around with other people.

Not all lines are created equal

Though humans have likely been forming lines of some sort for millennia, it was Scottish historian Thomas Carlyle who first mentioned the concept of a “queue” in his 1837 history of the French Revolution. He recalled patrons lined up outside bakeries in famine-plagued Paris. “The first come be the first served,” he wrote.

Fairness is perhaps the fundamental reason people put up with standing in lines, says Donald Norman, a cognitive design expert and author of the research paper The Psychology of Waiting Lines. “People get really annoyed when they feel that they’re not being treated like everyone else, and that there are people that seem to get ahead of them,” says Norman.

MIT professor Dick Larson, and self-proclaimed “Dr. Queue,” agrees. “The number one complaint from queuers is not the magnitude of the delay, it’s the unfairness, particularly when people cut in front of you.”

The modern travel industry has undermined the egalitarian basis for queues with a pay-for-sooner-play approach to the waiting game. A little (or a lot) of extra cash allows you to jump ahead with first-class airplane boarding, TSA PreCheck, or “skip-the-line” tickets to the Eiffel Tower or the Vatican. Critics say these practices create an inequitable, tiered experience; proponents argue that, for some vacationers, time is money. “Where there is a demand, there will be a market,” says Larson.

Still, the perception of fairness can be more powerful than reality. Said to have been pioneered at fast-food joint Wendy’s, a single, serpentine line means customers proceed on a first-come, first-serve basis. And studies show that people prefer a single line—compared with having to pick from multiple parallel ones—and feeling as if they’ve chosen the slowest one. 

For that reason, Larson predicts that the COVID-19 pandemic’s six-feet apart, social-distancing floor stickers may be here to stay. “They assure the sense of social justice, first-come, first-serve, not just for social distancing, but also to keep people in line,” he says.

How you pass time is important

Physicists have long theorized that time is a human construct. After all, a five-minute wait when there’s nothing happening seems infinitely longer than the same five minutes spent playing a game on your phone. Occupied time feels shorter. “When people are bored, they get grouchy and irritable,” says Norman. Menus distributed to customers in line, magazines at the dentist office, and TVs in airport waiting areas are all designed to keep guests distracted.

When it comes to entertaining people in line, amusement parks were pioneers. In the 1930s, Knott’s Berry Farm in Buena Park, California, became one of the first theme parks in the U.S. because thousands of people were regularly lingering outside the fruit stand and restaurant to eat Cordelia Knott’s fried chicken. “To entertain guests while they waited to hear their name called over a loudspeaker from the restaurant,” Cordelia’s husband Walter (co-owner and berry farmer) assembled a hodgepodge of items—covered wagons, live monkeys on leashes, an 800-year-old redwood tree stump, says Knott’s historian Eric Lynxwiler. That turned the place into a roadside attraction and eventually, a theme park equipped with gravity-defying roller coasters.

The Knotts may have originated the theme-park line, but neighboring Disneyland in Anaheim, California, refined the waiting game. “Disney invented all sorts of schemes to make lines tolerable,” Norman says. “They wanted you to stay in the park the whole day, but they didn’t have enough rides to keep you busy the whole time.” (National Geographic Partners is part of the Walt Disney Company.)

Prior to going on a log flume or other ride, Disney guests file through rooms or corridors where they’ll learn about the background and history of the attraction. “The Indiana Jones Adventure: The Temple of the Forbidden Eye” ride at Disneyland has a half-mile-long queue snaking through a dimly lit faux “ancient” temple where visitors can decipher cryptic petroglyphs on the walls or hear archeologists making excavations. “It’s a way of making the waiting line seem like part of the entertainment,” Norman says.

Another strategy some theme parks and attractions employ? Posting estimated wait times, which are often longer than actual wait times. “One of the axioms of all service industries is to manage people’s expectations at one level and deliver higher than that,” says Larson. 

Tech to the rescue

Long lines can be frustrating and disruptive to travel. When manpower is short, some companies and attractions are harnessing technology to reduce wait times. To avoid visitor bottlenecks, California’s Yosemite National Park and Colorado’s Rocky Mountain National Park recently implemented online reservation systems with assigned time slots. 

Theme parks use tech too. Universal Orlando has an app that tracks waiting times and allows customers to book spots in the queue; attractions from Dollywood in Pigeon Forge, Tennessee, to Ohio’s rollercoaster-rich Cedar Point employ scannable skip-the-line wristbands.

Airline queues are going digital, too. Passengers on Southwest Airlines flights can now get their spot in line 24 hours before wheels up. The airlines’ cattle-car boarding remains despite COVID-19, but technology enables early birds (and people with extra cash or mileage status) to nab priority boarding. In January 2020, Delta added a feature on its app notifying customers when to board, a process similar to restaurant pagers that buzz diners when their tables are ready.  

Airports worldwide are also embracing technology to trim lines. At the Dubai International Airport in the United Arab Emirates, passengers on Emirates airlines can check in, complete immigration forms, and board planes via biometric facial and iris recognition technology that verifies passengers’ identities. Lufthansa, Air Canada, Nippon Airways, Japan Airlines, and TEVA Air all offer similar programs at select airports.

Due to a surge in wanderlust-filled travelers and a shortage of workers, long lines are likely to continue all summer. In the meantime, Larson hopes that travelers will embrace queues as another part of their vacation experience. “I hope to see an increase in sophisticated tourists,” he says, “who will look into these delays as just part of the trip itself.”

Hospital Payments and the COVID-19 Death Count

Q: Are hospitals inflating the number of COVID-19 cases and deaths so they can be paid more?

A: Recent legislation pays hospitals higher Medicare rates for COVID-19 patients and treatment, but there is no evidence of fraudulent reporting.


Are hospitals getting 13,000 per patient if they write that on the diagnosis is COVID19 on the patient’s chart, and 35,000 for each patient if they are on ventilators?

I keep seeing posts in social media claiming that hospitals are over-stating covid-19 deaths because the they are paid more for these deaths … The YouTube video link here is attributed to Fox News with the headline “US: Hospitals Get Paid More to List Patients as COVID-19…” Can you provide any clarification?


A Minnesota state senator’s recent interview on Fox News about Medicare payments for COVID-19 hospitalizations has generated a frenzy of headlines on social media suggesting that hospitals may have a financial motivation when it comes to classifying cases or deaths as related to COVID-19.

One website ran a story headlined, “US Hospitals Getting Paid More to Label Cause of Death as ‘Coronavirus.’” It called the information “disturbing” and the interview “bone-chilling.”

Numerous readers have asked us about such claims, some of which imply that hospitals are making money by simply listing patients as having the disease — when in fact the payments referenced are for treating patients. And while some of the posts imply that fraud may be afoot, multiple experts told us that such theories of hospitals deliberately miscoding patients as COVID-19 are not supported by any evidence. 

The initial comment was made by Minnesota State Sen. Scott Jensen, a family physician, who spoke with Fox News host Laura Ingraham on April 8 about the idea that the number of COVID-19 deaths may be inflated. Jensen was responding to National Institute of Allergy and Infectious Diseases Director Anthony Fauci, who — while answering a reporter’s question about that theory — said “you will always have conspiracy theories when you have very challenging public health crises. They are nothing but distractions.”

Jensen, April 8: I would remind him that anytime health care intersects with dollars it gets awkward. Right now Medicare has determined that if you have a COVID-19 admission to the hospital, you’ll get paid $13,000. If that COVID-19 patient goes on a ventilator, you get $39,000, three times as much. Nobody can tell me after 35 years in the world of medicine that sometimes those kinds of things impact on what we do.

In an interview with, however, Jensen said he did not think that hospitals were intentionally misclassifying cases for financial reasons.

But that’s how his comments have been widely interpreted and paraded on social media. One YouTube video with Jensen’s interview, viewed 42,000 times, was titled “US: Hospitals Get Paid More to List Patients as COVID-19…” That video was then posted in a Facebook group called “X22 Report [Geopolitical]” with a caption referencing the specific dollar amounts that read in part: “This also explains the inflated amount of covid deaths.” Nearly 3,000 users shared the video from that post.

“So, hospitals get an extra $13,000 if they diagnose a death as COVID-19,” a widely shared meme on Facebook claimed. “And an additional $39,000 if they use a ventilator!” One post of the meme, shared by hundreds, was captioned: “And then we wonder why the numbers of deaths are embellished…”

The figures cited by Jensen generally square with estimated Medicare payments for COVID-19 hospitalizations, based on average Medicare payments for patients with similar diagnoses.

Medicare — the federal health insurance program for Americans 65 and older, a central at-risk population when it comes to COVID-19 — pays hospitals in part using fixed rates at discharge based off a grouping system known as diagnosis-related groups.

The Centers for Medicare & Medicaid Services has classified COVID-19 cases with existing groups for respiratory infections and inflammations. A CMS spokesperson told us exact payments vary, depending on a patient’s principal diagnosis and severity, as well as treatments and procedures. There are also geographic variations.

An analysis by the Kaiser Family Foundation looked at average Medicare payments for hospital admissions for the existing diagnosis-related groups and noted that the “average Medicare payment for respiratory infections and inflammations with major comorbidities or complications in 2017 … was $13,297. For more severe hospitalizations, we use the average Medicare payment for a respiratory system diagnosis with ventilator support for greater than 96 hours, which was $40,218.”

It is true, however, that the government will pay more to hospitals for COVID-19 cases in two senses: By paying an additional 20% on top of traditional Medicare rates for COVID-19 patients during the public health emergency, and by reimbursing hospitals for treating the uninsured patients with the disease (at that enhanced Medicare rate).

Both of those provisions stem from the Coronavirus Aid, Relief, and Economic Security Act, or CARES Act.

The CARES Act created the 20% add-on to be paid for Medicare patients with COVID-19. The act further created a $100 billion fund that is being used to financially assist hospitals — a “portion” of which will be “used to reimburse healthcare providers, at Medicare rates, for COVID-related treatment of the uninsured,” according to the U.S. Department of Health and Human Services.

As the Kaiser analysis noted, though, “it is unclear whether the new fund will be able to cover the costs of the uninsured in addition to other needs, such as the purchase of medical supplies and the construction of temporary facilities.”

Either way, the fact that government programs are paying hospitals for treating patients who have COVID-19 isn’t on its own representative of anything nefarious.

“There’s an implication here that hospitals are over-reporting their COVID patients because they have an economic advantage of doing so, [which] is really an outrageous claim,” Gerald Kominski, senior fellow at the UCLA Center for Health Policy Research, told us. And, he said, any suggestion that patients may be put on ventilators out of financial gain, not medical need, “is basically saying physicians are violating their Hippocratic Oath … it would be like providing heart surgery on someone who doesn’t need it.”

Robert Berenson, an institute fellow at the Urban Institute, said the notion that hospitals are profiting off the pandemic — as some of the social media posts may imply — isn’t borne out by facts, either.

Berenson said revenues appear to be down for hospitals this quarter because many have suspended elective procedures, which are key to their revenue, forcing some hospitals to cut staff. He surmised that potential instances of patients being wrongly “upcoded” — or classified as COVID-19 when they’re not — are “trivial compared to these other forces that are affecting hospital finances.”

Berenson and others we spoke with also said that hospitals have profound disincentives for “upcoding,” which can result in criminal or civil liabilities, such as being susceptible to being kicked out of the Medicare program.

Jensen himself said in a phone interview that he was not alleging widespread medical fraud.

“Do I think people are misclassifying? No,” Jensen said. He said his concerns centered on what he deemed “less precise standards” for certifying deaths promulgated by the U.S. Centers for Disease Control and Prevention, and how deaths classified as COVID-19 without corroborating positive test results could lead to an over-counting.

The CDC guidance says that officials should report deaths in which the patient tested positive for COVID-19 — or, if a test isn’t available, “if the circumstances are compelling within a reasonable degree of certainty.” It further indicates that if a “definite diagnosis of COVID–19 cannot be made, but it is suspected or likely (e.g., the circumstances are compelling within a reasonable degree of certainty), it is acceptable to report COVID-19 on a death certificate as ‘probable’ or ‘presumed.’”

“If we think it’s presumptive … we can go ahead and put down COVID-19,” Jensen said, “or even in some situations, even if it’s negative.” He pointed to the example of a 38-year-old man in Minnesota whose death was attributed to the coronavirus even though he tested negative.

The man’s mother, however, told the St. Paul Pioneer Press that doctors determined the test result was likely a false negative. It’s not known exactly how common false negatives are in the U.S., but public health experts and doctors have raised concerns about many instances of tests showing negative results even when all other indicators point to COVID-19.

Fact sheets for different COVID-19 tests from the Food and Drug Administration note that a “negative result does not exclude the possibility of COVID-19. When diagnostic testing is negative, the possibility of a false negative result should be considered in the context of a patient’s recent exposures and the presence of clinical signs and symptoms consistent with COVID-19. The possibility of a false negative result should especially be considered if the patient’s recent exposures or clinical presentation indicate that COVID-19 is likely, and diagnostic tests for other causes of illness (e.g., other respiratory illness) are negative.”

As for the accuracy of the death toll, other experts have previously told us that while it’s true that some deaths attributed to COVID-19 likely would have occurred regardless of the disease, other factors — like the deaths of undiagnosed COVID-19 victims, including those that occur at home — contribute to a more significant problem of under-counting the deaths.

New York City recently added more than 3,700 victims to its death toll to account for presumed cases. The CDC’s national count now makes note of how many cases and deaths were deemed “probable.” 

Jensen said he actually believed there could be both instances of under-counting and over-counting of COVID-19 cases and deaths — but said that “if there’s an over-count it’s conceivable that that could down the road translate to increased dollars in terms of some of the recovery dollars from COVID-19.”

When it comes to the $100 billion fund to help providers, future grants by HHS are supposed to focus on providers in areas hit hard by the outbreak, among others. But the initial allocation of $30 billion from that $100 billion fund to assist hospitals wasn’t distributed in that way. Instead, it was based on prior Medicare business.

A Kaiser Health News analysis found that the distribution of that initial $30 billion resulted in hospitals in states less affected by the pandemic — such as Minnesota, Nebraska and Montana — being given funding that worked out to be about “$300,000 per reported COVID-19 case.” In New York, which has the highest number of COVID-19 cases, the grant money amounted to “only $12,000 per case.”

CDC, FDA, NIH—what’s the difference?

The U.S. agencies all play an important role in addressing the COVID-19 pandemic, but each evolved from a unique moment in public health history.

If you get confused by the alphabet soup of agencies managing the United States’ response to the COVID-19 pandemic, you’re not alone. NIH. FDA. CDC: What are their missions, and how do their roles differ?

Although the National Institutes of Health (NIH), Food and Drug Administration (FDA), and Centers for Disease Control and Prevention (CDC) all respond to emerging and ongoing medical needs in the U.S., from infectious disease to mental health, they play different roles in fighting COVID-19 at home and abroad. And their mandates have evolved along with the nation and its changing public health needs.

A nation without public health surveillance

Healthcare wasn’t part of the plan when the U.S. was founded. At the time, epidemics were rampant and life expectancies low and the medical profession was not standardized, formally trained or licensed.

The Centers for Disease Control and Prevention (CDC) was originally tasked with eradicating malaria in the American South by using measures such as spraying for disease carrying mosquitoes.PHOTOGRAPH VIA SCIENCE HISTORY IMAGES, ALAMY STOCK PHOTO

Although the government did carry out some public health efforts, it lacked a centralized health body and its actions were mostly on behalf of the military. In 1777, for example, George Washington instigated mandatory inoculation against smallpox for all Continental Army troops.

It would take almost half a century for modern medicine to emerge in the West, and for public health to become a national priority. As wars, contagious diseases like cholera and influenza, and unregulated foods and medicines threatened lives in the 19th century, several federal agencies tasked with improving and protecting public health were born.

U.S. Food and Drug Administration (FDA)

The U.S. government began its first investigations into food and other consumable products in response to a 19th-century wave of adulterated or counterfeit patent medicines and poisonous food additives. In the 1880s, Harvey Washington Wiley, a scientist with the U.S. Department of Agriculture’s Bureau of Chemistry—he was known as the “Crusading Chemist”—pushed for tighter regulations over food and medicine, even conducting highly publicized experiments in which he fed healthy men tainted food.

As a result of intense lobbying by Wiley and other reformers, legislators passed the Pure Food and Drugs Act of 1906, which made it a crime to sell adulterated or poisonous food or drugs. The U.S. Department of Agriculture’s Bureau of Chemistry was tasked with regulation, and the Food and Drug Administration was born.

Federal meat inspectors examine butchered meat in 1910. Part of the FDA mandate is to assure the safety of the U.S. food supply.ALAMY STOCK PHOTO

The agency, which gained its formal name in 1930, has a largely regulatory role in public health. It supervises drugs, medical devices, and clinical trials, and enforces the Federal Food, Drug, and Cosmetic Act.

During the COVID-19 pandemic, the FDA has issued hundreds of emergency use authorizations, which speeds up the authorization process for drugs like vaccines and devices like masks. It has also taken action against pandemic-related fraud, issuing warning letters and fines and bringing cases against companies selling everything from fraudulent “medicines” to adulterated and unapproved tests for the disease.

National Institutes of Health (NIH)

Another division of the Department of Health and Human Services, the National Institutes of Health has roots in the nation’s earliest health law, a 1798 statute deducting money from seamen’s salaries for medical care and hospitals. In 1870, the nation’s 31 marine hospitals were consolidated under the Marine Hospital Service (MHS) to create the Public Health Service, a commissioned corps of medical officers devoted to public health.

The MHS’s mandate ballooned in the late 19th century, when it took over the inspection of incoming ships and immigrants to U.S. ports. Tasked with examining passengers for signs of cholera and other highly contagious diseases and enforcing quarantines, its physicians became increasingly interested in the emerging science of infectious disease.

Public health workers pose in front of the Marine Hospital Service (MHS) headquarters in an undated photo. Responsible for inspecting incoming ships for disease and enforcing quarantines, the physicians of the MHS, later the National Institute of Health, beca…Read MoreALAMY STOCK PHOTO

During subsequent health crises, the agency became more involved in medical research. It began to award research grants, and in 1930 changed its name to the National Institute of Health (the plural was adopted in 1948, reflecting the addition of research arms for everything from cancer to heart disease). Today, the organization has 27 different institutes and centers, including the National Library of Medicine and National Institute of Mental Health.

One of them, the National Institute of Allergy and Infectious Diseases, led by Anthony Fauci, has been in the spotlight during the COVID-19 pandemic. The larger agency is approaching the disease from a variety of fronts and disseminating the latest research as it evolves. To date, the federal government has allocated nearly $4.9 billion to the NIH—funding earmarked for research on tests, vaccines, and treatments.

Centers for Disease Control and Prevention (CDC)

Although today it’s the most visible federal agency devoted to public health, the Centers for Disease Control and Prevention (CDC) has humble roots. It started out as the Office of Malaria Control in War Areas, an obscure branch of the Public Health Service founded in 1942.

The Atlanta headquarters of the CDC, shown in 1976. Today, the agency plays a major role in monitoring the pandemic and…Read MoreASSOCIATED PRESS

At the time, malaria was still common in the South, where many military bases were located. The agency eliminated mosquito hotspots, trained local officials, educated the public, and developed malaria prevention techniques for troops deployed to the Pacific Theater during World War II. The initiative was so effective that, in 1946, a Communicable Disease Center (CDC) was opened in Atlanta.

At first, the organization was devoted purely to malaria prevention, and its efforts helped eradicate the disease from the U.S. by 1951. Then the CDC expanded, addressing everything from polio to rabies and becoming the official agency to deal with health in public disasters. Today, it’s the nation’s official health protection agency, tasked with informing the public, gathering statistics, detecting and responding to health threats, and eliminating disease.

During COVID-19, the CDC has developed tests to detect and monitor the disease, prepared guidance for public health departments and the public, directed money to healthcare facilities, and communicated with the public about every aspect of the pandemic.

Fighting COVID-19

All three agencies are part of the U.S. Department of Health and Human Services, and their budgets grew with the pandemic. The CDC’s budget far outpaced the other agencies, though, reflecting the scale of both the pandemic and the agency’s national and global response.

But are the agencies prepared for the pandemic of the future? Not necessarily, experts say.

In an October 2020 report on pandemic preparedness, the Council on Foreign Relations, a nonpartisan think tank, called both the state and federal response to the pandemic “deeply flawed.” Without expanded investment in preparedness and a more coordinated response from the federal government, the report says, the nation won’t be able to face the unknown—but not unforeseen— public health challenges of the future.

“The virtual inevitability and high potential toll of future pandemics make investments in preventive and mitigatory measures both sensible and cost effective,” the report says. “The amount required to prevent and mitigate such incidents pales in comparison to their costs.”

The Mu variant is on the rise. Scientists weigh in on how much to worry.

Laboratory studies suggest this variant may be better at avoiding the immune system but lags Delta when it comes to transmission and infecting cells.

(Update 9/11/2021)

One of the newest variants of COVID-19, known as Mu, has spread to 42 countries, but early studies suggest that it is less easily transmitted than the dangerous Delta variant, which has triggered a resurgence of the pandemic in the U.S. and many other countries.

Mu quickly became the dominant strain in Colombia, where it was first detected in January, but in the U.S., where the Delta virus is dominant, it has not spread significantly. After reaching a peak at the end of June, the prevalence of the Mu variant in the U.S. has steadily declined.

Scientists believe that the new variant cannot compete with the Delta variant, which is highly contagious. “Whether it could have gone higher or not if there was no Delta, that’s hard to really say,” says Alex Bolze, a geneticist at the genomics company Helix.

In Colombia, however, the Mu variant is responsible for more than a third of the COVID-19 cases. There have been 11 noteworthy variants to date, which the World Health Organization has named for the letters of the Greek alphabet. The newest variant, Mu, is the 12th. WHO has labeled this latest version of SARS-CoV-2 a Variant of Interest, a step below a Variant of Concern. 

Delta and three other variants have drawn the highest level of concern. But a Variant of Interest, like Mu still raises worries. Mu has many known mutations that can help the virus escape immunity from vaccines or previous infection.

Still, the good news is that Mu is unlikely to replace Delta in places like the U.S. where it is already predominant, says Tom Wenseleers, evolutionary biologist and biostatistician at the Catholic University of Leuven in Belgium, who previously estimated the transmissibility and impact of Alpha variant in England.

How is Mu different? 

Most genetic sequences reveal that Mu has eight mutations in its spike protein, many of which are also present in variants of concern: Alpha, Beta, Gamma, and Delta.

Some of Mu’s mutations, like E484K and N501Yhelp other variants evade antibodies from mRNA vaccines. In the Beta and Gamma variants, the E484K mutation made the variants more resistant to a single dose of mRNA vaccines.

A study, not yet peer reviewed, has shown that the P681H mutation helps transmission of the Alpha variant—it may do the same for Mu. 

Mu also harbors novel mutations that haven’t been seen in variants before, so their consequences are not fully understood. Mutation at the 346 position disrupts interaction of antibodies with the spike protein, which, scientists say, might make it easier for the virus to escape.

A study using epidemiological models, not yet peer reviewed, estimates that Mu is up to twice more transmissible than the original SARS-CoV-2 and caused the wave of COVID-19 deaths in Bogotá, Colombia in May, 2021. This study also suggests that immunity from a previous infection by the ancestral virus was 37 percent less effective in protecting against Mu.

“Right now, we do not have [enough] available evidence that may suggest that indeed this new variant Mu is associated with a significant [..] change in COVID,” says Alfonso Rodriguez-Morales, the President of the Colombian Association of Infectious Diseases.

But some clues are emerging that Mu can weaken protection from antibodies generated by existing vaccines. Lab-made virus mimicking the Mu variant were less affected by antibodies from people who had recovered from COVID-19 or were vaccinated with Pfizer’s Comiranty. In this study, not yet peer reviewed, Mu was the most vaccine resistant of all currently recognized variants.

In another lab-based study, antibodies from patients immunized with Pfizer’s vaccine were less effective at neutralizing Mu compared to other variants. 

“[Mu] variant has a constellation of mutations that suggests that it would evade certain antibodies—not only monoclonal antibodies, but vaccine and convalescent serum-induced antibodies—but there isn’t a lot of clinical data to suggest that. It is mostly laboratory […] data,” said Anthony Fauci, director of the National Institute of Allergy and Infectious Diseases, at a White House press briefing on September 2.

The COVID-19 vaccines—Pfizer, Astra Zeneca, Johnson & Johnson, and Sinovac, all of which are available in Colombia—still seem to offer good protection against Mu, according to Rodriguez-Morales.

How prevalent is Mu?

The Mu variant rapidly expanded across South America, but it is difficult to know for sure how far Mu has spread, according to Paúl Cárdenas, microbiologist at Universidad San Francisco de Quito in Ecuador.

“[Latin American countries] have provided very low numbers of sequences, compared with the numbers of cases that we have,” says Cárdenas. South American countries have sequenced just 0.07 percent of their total SARS-CoV-2 positive cases, although 25 percent of global infections have occurred in the region. This contrasts with 1.5 percent of all positive cases sequenced in the U.S. and 9.3 percent of all positive cases sequenced in the U.K.

“We are not necessarily looking at the reality of the distribution of the variants [in Latin America], because of the limitations in performing genome sequencing,” says Rodriguez-Morales.

That said, except in Columbia where Mu has been spreading since late February, the variant is becoming relatively less frequent globally, including in the rest of South America.

“Additional evidence on Mu is scarce, similar to Lambda and other regionally prevalent variants, because of limited capacity for follow-up studies, and because these variants have not yet been a significant threat in high-income countries like Delta is,” says Pablo Tsukayama, a microbiologist at Universidad Peruana Cayetano Heredia in Lima, Peru. He hopes the WHO’s designation of Mu as a variant of interest will change that.

The epic COVID-19 memorial on the National Mall, in one stunning photo

4,882 photos taken over 30 hours. More than 670,000 flags representing American lives lost. An incalculable measure of grief.

(Update 10/1/2021)

For more than 30 hours, photographer and National Geographic Explorer Stephen Wilkes watched people move through the sea of white flags below him on the National Mall in Washington, D.C. He saw young children bend down curiously to examine the small flags, and cyclists lay down their bikes to take in the 20-acre expanse of them. He saw skateboarders roll through, selfie-takers frame shots—and passersby slowly realize that each flag represents a life lost to COVID-19.

On September 18 and 19, starting before sunrise and finishing after sunset, Wilkes took 4,882 photographs of the art installation In America: Rememberan exhibit that aims to convey the enormity of the country’s pandemic losses. He and his team then blended the photographs into a single composite image, part of his Day to Night series.

“One of the things I tried to capture was the epic scale of this,” says Wilkes. “It’s almost impossible to take it all in.”

people walking near the Covid-19 memorial in Washington D.C.
A close up of the photograph provides a glimpse of Suzanne Firstenberg, the artist who created the installation, approaching the intersection of paths from the left in a blue hat and a backpack.PHOTOGRAPH BY STEPHEN WILKES

To do so, Wilkes spent two days suspended 45 feet above the ground in a lift—high enough for a bird’s eye view but low enough to descry people’s gestures and body language. He positioned the lift purposely: He wanted the National Museum of African American History and Culture (shown on the left with the sun rising over it) to be a focal point because “so many people of color were dramatically impacted by this virus.”

a gif of a photographer on a cherry picker photographing the flags memorializing Covid deaths in Washington D.C.
Photographer Stephen Wilkes, right, and Lenny Christopher, his assistant, were elevated 45 feet for a total of 30 hours to photograph the flag installation on the National Mall in Washington, D.C.VIDEO BY STEPHEN WILKES

The walkway was another focal point, which he used to draw viewers into the picture. In a bit of serendipity that he attributes to “the magic that sometimes happens when I photograph,” a sweeping cloud formed near the Washington Monument. “The path takes you up into the image,” Wilkes says, “and the clouds pull you around it.”

His camera angle was fixed in place so that all photos were shot from a single viewpoint. When he spotted “little moments, little vignettes,” he pressed the shutter.

Over the 13 years that Wilkes has been embarked on his Day to Night project, he’s photographed many significant events (presidential inaugurations, the 2020 Commitment March, the Tour de France) and iconic places (Yosemite, Coney Island, the Western Wall in Jerusalem). This one was different, he says, “because this was about a loss of life that’s unprecedented in American history.”

Suzanne Firstenberg, the visual artist who created In America, designed the installation to help people make sense of the staggering numbers. Those who lost a loved one to COVID-19 can personalize a flag with their name and a message or make a request through the exhibit’s website for a volunteer to inscribe a flag for them.

When visitors encounter those flags, Firstenberg wants them to think, “Oh my God, this person was a father, a mother, an uncle. The family’s grief must be immense,” she says, speaking two days before the exhibit opened on September 17. “The coworkers, the faith communities, the neighbors, all those concentric circles of grief surrounding that one flag—and then you lift your gaze, and you look at 660,000 other flags. It captures the essence of one family’s grief and yet magnifies it to the nation.”

When Firstenberg was planning the exhibit, she ordered 630,000 flags—preparing for what she thought would be the worst-case scenario. Soon she realized she’d have to order many more. On opening day, the death toll surpassed 670,000. Three days before the exhibit’s live-streamed closing ceremony on October 3, it’s topped 693,000.

It would have been easy, says Wilkes, to make an image that dwelled upon the darkness of so much death. But Firstenberg created the installation to appeal to our common humanity, so “I wanted the image to reflect the sense of hope that we’re going to come forward out of this,” he says. “It’s a moment of reflection. And maybe a moment when we need to come together.”

Why even fully vaccinated older people are at high risk for severe COVID-19

Many factors weaken the aging immune system. But vaccines—and booster doses—do offer protection from hospitalization and death.

(Update 10/22/2021)

Mounting data suggest that older people are at higher risk of severe disease from a breakthrough infection of COVID-19—and scientists say that should come as no surprise. After all, older age brackets have been disproportionately at risk throughout the pandemic, and that continues to be true even once someone is fully vaccinated.

Concerns about breakthrough infections bubbled up again this week when news broke on October 18 that former Secretary of State Colin Powell had died after contracting COVID-19. Powell was 84, but his cause of death was more complex: The former statesman suffered from multiple myeloma, a cancer of white blood cells. People with this form of cancer tend not to respond well to vaccines.

But in addition to the immunocompromised, health officials are seeing worrying evidence that older age groups continue to be at higher risk from the pandemic. According to the latest data from the Centers for Disease Control and Prevention, people over 65 account for 67 percent of hospitalizations and 85 percent of deaths from breakthrough cases. And recent media reports citing data from Seattle, Washington, and the United Kingdom show that older vaccinated people face similar—and, in some cases, greater—risks of severe disease than unvaccinated children.

“The huge risk factor is age,” says William Petri, an immunologist at the University of Virginia. That’s why the U.S. prioritized vaccinating older people and those in long-term care facilities when it first rolled out the vaccines, he explains. “If you’re under 45, your chances of dying are almost nonexistent, and then it increases exponentially.”

Concerns over breakthrough infections are also why U.S. regulators have approved booster doses of the Pfizer vaccine for people over 65—and are poised to do the same for the Moderna and Johnson & Johnson jabs.

Here’s what scientists know about the aging immune system—and why breakthrough infections don’t change the fact that COVID-19 vaccines remain remarkably effective for people at any age.

Aging immune systems

Experts say they still don’t have an adequate explanation for why older people were more susceptible to COVID-19 even before vaccines were available. “It’s just one of the great mysteries of the virus,” says Deepta Bhattacharya, an immunologist at the University of Arizona.

Scientists who study aging say it likely has to do with some of the hallmarks of getting older. For example, the human body normally clears away cells that have become damaged due to disease, injury, or stress. But as the body ages, this process becomes less efficient, and it starts to accumulate so-called senescent cells, which are damaged but won’t die. These cells secrete chemicals that damage neighboring healthy cells and trigger inflammation. Senescent cells thus weaken the body and make it harder to fight off infections.

But there’s a lot more going on in an aging body, and many elements of aging likely work together to undermine the immune response, says Eric Verdin, president and chief executive officer of the Buck Institute for Research on Aging, a biomedical research group based in California.

Among older people, he says, there are two broad abnormalities of the immune system: a hyperactive innate response, and an underactive adaptive response.

Innate immunity is the defense system you were born with—and the first to respond to invaders. It doesn’t target a specific pathogen, but rather mounts a generic inflammatory response. When that response is inappropriately intense, as happens in older people, it can trigger a cascade of damage throughout the body, from the lungs to the heart to the kidneys.

The adaptive immune response targets a specific invading pathogen. Vaccines provide a preview of the germ and teach the body how to create antibodies that recognize and latch onto a virus and block it from entering any of the body’s cells. If the virus does manage to break through, then T cells join in and kill the infected cell. Verdin likens it to an army that defends the body from attackers. If the amount of virus is small, the antibodies and T cells can easily defeat it.

A larger viral force, however, can overwhelm the adaptive immune system. Older people, who are less able to mount a vigorous adaptive response, may therefore be particularly susceptible to breakthrough infections.

“Everything gets worse with age, is the bottom line,” Bhattacharya says.

Breakthrough infections

Annual flu shot drives have shown that age can dampen the effectiveness of some vaccines. Verdin says a third of people over age 70 don’t respond at all to the flu vaccine, which is why it still kills a disproportionate number of older Americans every year.

On the other hand, responses to COVID-19 vaccines have been a lot stronger. “I think one of the more surprising things is how well the mRNA vaccines did with those older populations,” Bhattacharya says. “If you look at the initial immune responses, they weren’t very much different at all between people over 65 and those below. So that was a pretty pleasant surprise.”

However, in September the CDC reported that the vaccines are only about 78 percent effective at preventing infection among people of all ages after six months. It’s unclear exactly what is responsible for this drop in effectiveness. Bhattacharya says some studies do show that immunity is waning in people over 65, but he points out that it could also be caused by the rise of the Delta variant, which has proven better able to evade the body’s immune response.

In late September, New York magazine’s David Wallace-Wells wrote of “the overwhelming age skew of the disease” even among the vaccinated, citing data from the United Kingdom showing that vaccinated people over 60 died from COVID-19 at higher rates than unvaccinated people under 50. The New York Times also recently wrote about hospitalization rates in the Seattle area, which show that the risks for vaccinated people in their 50s are similar to the risks for unvaccinated children under age 15.

Bhattacharya says he doesn’t like comparing the two age groups, arguing that it’s much more important to compare the risks among unvaccinated versus vaccinated people no matter their age. These data clearly show that everyone benefits from a vaccine: In the U.K., for instance, the death rate for unvaccinated adults is several times higher than it is for vaccinated adults in every age group.

And despite the drop in effectiveness in preventing infection, the Pfizer vaccine remains 90 percent effective at preventing hospitalization, which shows that it remains a solid defense against severe disease and death. A recent report published by the U.S. Department of Health and Human Services said that vaccines “may have helped prevent hundreds of thousands of new COVID-19 infections and tens of thousands of deaths among seniors.”

Bhattacharya says that federal regulators in the U.S. have approved boosters for people over 65—and not the general population—because of the extra risks that they face. He and other scientists emphasize that high-profile breakthrough infections and the approval of booster shots should not discourage anyone from getting vaccinated. On the contrary, it should be seen as confirmation that the vaccines work.

“Rest assured, these are the best vaccines we’ve ever had,” Petri says.

Verdin agrees: “Getting vaccinated really puts things on your side. Think about it as a war where you want to have all the ammunition that you can possibly have.”

How coronavirus compares to flu, Ebola, and other major outbreaks

Weighing diseases against each other is a complicated calculus. These charts explain why.

(Update 10/22/2021)

The novel coronavirus that originated in Wuhan, China, has swept across the globe, infecting about 31,500 people as of press time. But a persistent question has permeated the public consciousness: Is this new viral terror less or more dangerous than other infectious diseases?

Every major epidemic spawns some brand of this mental exercise, and for good reason. Health officials and regular citizens set their priorities based on the general risk to the public. This week, the World Health Organization announced plans to dole out $675 million on the barely month-old outbreak of novel coronavirus. By contrast, the agency has raised a third of this amount from international partners to combat the Ebola epidemic in central Africa, which has been raging since August 2018.

Pitting these hazards against each other calls on a complicated calculus, which weighs factors like how contagious a disease is versus fatalities and severe outcomes, versus the socioeconomic ramifications of locking down a region.

Even a simple comparison of death rates can struggle to yield a judgment on the worst infectious foe. For example, influenza—whether it be seasonal or an emerging strain like H1N1—can infect millions of people, but it kills a relatively low portion of its cases, about 0.1 percent. Pandemic coronaviruses—like SARS, MERS, and the novel strain from China—are far more severe. SARS killed about 10 percent of its cases, but it only created about 8,000 confirmed infections.

At the moment, the novel coronavirus has far surpassed SARS in terms of known infections, and it has a case-fatality ratio of 2 percent: In effect, the coronavirus is 20 times as deadly as influenza. Some scientists argue that the novel virus will burn out quickly—but that’s not what happened with MERS, which has remained endemic in the Middle East since 2012.

So, the concern is that if the novel coronavirus reaches millions of people, it could be extremely harmful. Those worries are compounded by the fact that there is no specific treatment for the novel coronavirus, unlike with the flu vaccine. A human trial of an antiviral remedy called lopinavir-ritonavir would hopefully be completed in a month’s time, Maria Van Kerkhove, an infectious disease epidemiologist who tackled the MERS crisis and the technical leader for WHO’s Health Emergencies Program, added during the briefing. This drug combination has been used in the past to fight HIV.

In the meantime, it’s too early to tell how far the novel coronavirus might travel. That’s why there is so much emphasis on quarantines and on restricting the movements of infected people.

As draconian and old-school as it may seem, quarantine remains one of the most valuable ways to control outbreaks. WHO credits quarantines and isolation for ultimately containing the SARS outbreak. And given that coronavirus, like influenza, spreads via close contact and over short distances, physical separation makes sense to some degree.

The type of quarantine dictates its value as well. Research shows that hospital quarantines can be cost-effective, but at-home quarantines, social distancing, and travel restrictions come with the high price of disrupting commerce, even for low- and middle-income countries. China lost $55 billion in productivity during the 2009 H1N1 outbreak and $40 billion during the SARS episode, according to the Wall Street Journal. Those harsher modes of infection control also hinder the ability to measure disease burden and overall outcomes, for example, if people are kept from visiting hospitals.

Listing off priorities for the novel coronavirus, Van Kerkhove emphasized prevention of human-to-human transmission and early identification and isolation of patients. She added that the current standard of care depends on the severity of individual cases, but the worst cases require hospital-based, optimized treatments such as oxygen therapy, mechanical ventilation, and resuscitation.

“The global community around clinical management will be meeting to discuss the research needs to better care for patients infected with novel coronavirus,” Van Kerkhove says of a session scheduled for next week. “It is important that WHO work with partners and with all of you to ensure optimized standard of care at the hospital level.

How the rise of antivirals may change the course of the pandemic

Making them isn’t easy. But new pills to treat COVID-19 are now showing promise at curbing illness and saving lives.

(Update 1/6/2021)

Years before the rise of the COVID-19 pandemic, virologists started a quest to find drugs called antivirals that can protect people against emerging coronaviruses. The journey has been slow and failures have been frequent. But with Britain’s authorization this week of Merck’s new drug molnupiravir, and a cash infusion into antiviral R&D, the outlook for these treatments is getting much brighter.

Unlike vaccines that can prevent infection, antivirals act as a second line of defense, slowing down and eventually arresting progression of a disease when infections occur. They’re also important when effective vaccines aren’t available against viral diseases, as is the case for HIV, hepatitis C, and herpes.

But developing antivirals is an expensive and difficult endeavor. That’s especially true for acute respiratory diseases, for which the window for treatment is short. In the case of SARS-CoV-2, the coronavirus that has unleashed the devastating COVID-19 pandemic, researchers have resorted to repurposing old drugs or compounds that were being tested against other diseases.

“That’s typical,” says Katherine Seley-Radtke, a medicinal chemist at the University of Maryland, Baltimore County. “Every time a new virus emerges or an old one re-emerges, you pull out what’s there in the cupboard to see what works.”

So far remdesivir, originally developed by biopharmaceutical company Gilead Sciences for hepatitis C and Ebola infections, is the only antiviral drug approved by the U.S. Food and Drug Administration to treat COVID-19. It must be administered via injection while a patient is in the hospital, although there isn’t consensus regarding its ability to treat COVID-19.

Experts think oral antivirals like Merck’s are set to be the most promising tools to work alongside vaccines at combating the pandemic. Provided they are affordable, antivirals could be especially important among people who remain unvaccinated either out of choice or due to limited access and economic constraints.

“People don’t mind taking pills,” Seley-Radtke says. “You can stockpile them. You don’t need specifical conditions to store them. You can ship them all across the world.”

In June 2021 President Joe Biden announced an investment of more than a billion dollars to advance the development of antivirals for COVID-19. As part of the same plan, he also promised an additional $1.2 billion in funding toward discovering new compounds that can treat SARS-CoV-2 as well as other emerging viruses with pandemic potential.

“Finally, the government and funding agencies are taking it seriously,” Seley-Radtke says of antiviral development. “We cannot continue to sit back and wait for the next pandemic to occur. We have to be proactive. We have to be prepared.”

How antivirals work

Unlike bacteria, viruses can’t reproduce on their own. They rely on their host cell’s machinery to replicate. That means a virus must insert itself into a living cell and hijack its machinery to make thousands of copies of itself. These “offspring” then escape and go on to infect nearby host cells, spreading the disease inside the body and ultimately to new carriers.

Antiviral drugs often work by preventing the virus from attaching to or entering the host cell, or by obstructing its replication once it’s in there.

The drug remdesivir, for instance, mimics one of the genetic building blocks essential for SARS-CoV-2 to replicate; it then gets incorporated into the viral genome, stalling its replication. The experimental antiviral molnupiravir, developed by Ridgeback Biotherapeutics LP and Merck & Co., engages in similar mimicry and induces errors during viral replication.

“Then you reach a point where you have so many errors that the virus is unable to replicate,” says critical care virologist William Fischer at the University of North Carolina at Chapel Hill.

Pfizer’s experimental antiviral PF-07321332 also targets viral replication but does so by thwarting enzymes called proteases. SARS-CoV-2 and other viruses, such as HIV, use these enzymes to split large proteins into smaller fragments that then combine with viral genetic material to form new copies of the virus.

Many experts think targeting the human cell’s hijacked machinery can be highly effective, but the concern is that such antivirals could damage otherwise healthy cells, causing a range of side effects. Only targeting viral proteins isn’t a permanent fix either. “If you try to develop an antiviral against a particular viral protein, there is very quick evolutionary pressure on the virus to mutate and develop resistance,” says Tia Tummino, a pharmacologist at the University of California, San Francisco.

A more effective strategy is to use several of these antiviral drugs in combinations of two to four to target different viral proteins and life stages simultaneously, which is standard practice for fighting HIV or treating hepatitis C infections. “That makes it hard for a virus to escape,” Tummino says.

The complicated path to developing antivirals

However, developing safe and effective antivirals isn’t easy. Just over a hundred have been approved by the FDA since 1963, when the first antiviral, idoxuridine, was given the green light to treat herpes of the eye. More than a third of the FDA-approved antivirals are for HIV.

Historically antiviral drug development has focused on a “one bug, one drug” approach, which meant targeting proteins common to specific groups of viruses. While such antivirals can be extremely effective, viruses produce very few proteins of their own, giving drug makers limited options to target.

There’s also the risk of the drugs damaging cells. Some viral proteins can be unique, in that they don’t overlap with the ones produced by the host, making them ideal targets for antiviral drugs. But if the target proteins do overlap or perform the same functions as the human host cells, there’s potential for collateral damage, resulting in side effects.

One other challenge is the increasing diversity of viruses causing severe disease in humans, and thus the need for antivirals that work against a variety of these pathogens. Remdesivir targets a viral enzyme called polymerase, which has a genetic architecture that’s similar across different coronaviruses. But few such broad-spectrum antivirals exist because they often require complex design or they could lead to unanticipated side effects.

Once drugmakers have identified a target, the compound has to go through a lengthy testing phase. The first step involves demonstrating that the compound works on infected cells in Petri dishes, then assessing if it is safe and effective in laboratory animals and finally in clinical trials in humans. Sometimes with a new virus the challenge can be finding the right cells and relevant animal models to use in these trials. In the early days of hepatitis C research, for instance, chimpanzees were the only lab animals that could be experimentally infected with the virus, raising ethical concerns. It took a few years to develop genetically engineered mice that the virus could infect instead.

The entire process thus requires substantial funding. Because hepatitis C and HIV infections are chronic and affect millions of people across the world, they sustain the interest of for-profit pharmaceutical companies. “But when you think of medications available for acute respiratory diseases, you can count them on your hand,” says Timothy Sheahan, a virologist at the University of North Carolina at Chapel Hill. “The time in which you have to intervene and give therapy is really short,” which may not be a money-making enterprise unless lots of people are affected.

Coronaviruses were not even known to cause severe human disease until 2002-04, when the virus that causes SARS infected nearly 8,000 people worldwide and killed 774. That was followed a few years later by the Middle East Respiratory Syndrome (MERS) coronavirus, which infected more than 2,000 people and killed nearly 900—including six this year.

In the wake of SARS and MERS, virologists started investigating antivirals for coronaviruses—and then came the COVID-19 pandemic.

The race to develop antivirals against SARS-CoV-2

Normally making antiviral therapies for new viruses can take at least a decade. Unsurprisingly, the urgency presented by COVID-19 meant finding new ways to use old drugs.

“Repurposing is typical for understudied diseases and epidemics arising from new viruses,” Tummino says. “It cuts down time from discovery to the drug reaching humans.”

Researchers started screening molecular collections, such as the California Institute for Biomedical Research’s ReFRAME, to test if any FDA-approved drugs and investigational compounds were effective against SARS-CoV-2. Laura Riva, a computational biologist formerly at the Sanford Burnham Prebys Medical Discovery Institute in California, conducted one such screen along with her colleagues and identified more than a dozen compounds, including remdesivir, that blocked SARS-CoV-2 replication in animal and human cells.

In a June 2020 study involving monkeys, researchers observed remdesivir’s antiviral potential against SARS-CoV-2. And in one of the earliest clinical trials involving hospitalized COVID-19 patients, they noted its role in shortening recovery time. The experimental drug was granted approval in October 2020, making it the first FDA-approved COVID-19 treatment, despite lacking unequivocal support from other clinical trials.

However, identifying candidate antivirals without knowing what aspect of the virus’s biology they target is tricky. There’s also a risk that many compounds will turn out to have the same ineffective method of attack. For instance, 33 of the repurposed drugs tested, including the infamous hydroxychloroquine, were similar in that they accumulated fat-like substances in cells in Petri dishes that somehow reduced SARS-CoV-2 replication, but they weren’t quite as effective when tested in more than 300 COVID-19 clinical trials.

“That’s why I’m critical of repurposing drugs,” says Miguel Ángel Martínez, a clinical virologist at Spain’s IrsiCaixa AIDS Research Institute. “There is no shortcut to developing antivirals.”

Still, other experts think experimental antivirals like molnupiravir, which was first developed for influenza, hold potential to combat COVID-19.

Clinical trial outcomes spark hope

Unlike remdesivir, which is administered intravenously, molnupirvair can be swallowed as a pill. Meant for patients with mild to moderate COVID-19, the oral antiviral is taken within five days of symptoms surfacing. In an October 1 press release, drugmakers Merck and Ridgeback Biotherapeutics announced their phase 3 results, which indicated that taking the pill twice a day for five days cuts hospitalization and deaths among those infected by half.

Although these are interim findings that aren’t yet peer-reviewed, the companies jointly applied for an emergency use FDA authorization of the pill on October 11; the U.K. authorized molnupirvair’s use on November 4.

Another oral antiviral, favipiravir, also known as Avigan and first developed as an anti-flu pill in Japan, is undergoing clinical trials to assess if it can be used early in a COVID-19 infection. Previous favipiravir trials, albeit small, had suggested that in mild to moderate hospitalized COVID-19 patients, the drug could clear SARS-CoV-2 in their nose and throats. So far, countries including Japan, Russia, and India have approved its use to treat COVID-19.

Pfizer’s PF-07321332 experimental antiviral pill also aims to target SARS-CoV-2 infections early to prevent rapid viral replication. Developed as a potential treatment for SARS-CoV nearly two decades ago, the repurposed experimental drug is now being given in combination with a small dose of HIV antiviral ritonavir to COVID-19 patients in ongoing phase 2/3 clinical trials.

As of now, there are a handful of other experimental antivirals in early stages of clinical trials, and at least a few others might join the list.

“We’re experiencing an opportunity to test antivirals for an acute respiratory disease unlike any we’ve ever had,” says Sheahan. “Getting antivirals approved is worth celebrating. Getting more than one approved for a single disease will be even more amazing.”

Do vaccines protect against long COVID? What the data say

Vaccines reduce the risk of developing COVID-19 — but studies disagree on their protective effect against long COVID.

Allison Navis at Mount Sinai's Center for Post-COVID Care testing movement with a patient.
Allison Navis (left) assesses Esteban Giron at a clinic for people with post-COVID symptoms at Mount Sinai Hospital in New York City.Credit: Mount Sinai Health System

Physiotherapist David Putrino’s neurological rehabilitation clinics used to treat about 50 people each week with conditions such as chronic pain, Parkinson’s disease and sports injuries. Then came long COVID.

Now, Mount Sinai Hospital’s Abilities Research Center in New York City, one of three clinics that Putrino directs, treats another 50–100 people each week who are coping with issues such as extreme fatigue, breathlessness, difficulty concentrating or any of the many other symptoms of long COVID — the long-lasting, poorly understood syndrome that can occur after infection with the SARS-CoV-2 coronavirus. He has 1,600 clients with long COVID, and more on a waiting list.

Putrino has noticed that even being fully vaccinated doesn’t necessarily protect against long COVID. Many of his clients were infected before vaccines were rolled out, and had been coping with symptoms for a year or more before they were referred to him. But he has seen about a dozen people who experienced long COVID from ‘breakthrough’ infections — in which vaccinated people catch the coronavirus. “It is noticeably less common than in unvaccinated people, but it’s still there,” he says. He thinks that clinics could see more such cases as the months tick by.

Vaccines reduce the risk of long COVID by lowering the chances of contracting COVID-19 in the first place. But for those who do experience a breakthrough infection, studies suggest that vaccination might only halve the risk of long COVID — or have no effect on it at all1,2. Understanding the prevalence of long COVID among vaccinated people has urgent public-health implications as restrictions that limited viral spread are eased in some countries. It could also offer clues about what causes lingering COVID-19 symptoms long after the acute infection has cleared.

At present, public-health officials are flying blind when it comes to long COVID and vaccination. Although vaccines greatly reduce the rates of serious illness and death caused by COVID-19, they are not as effective at completely preventing the disease, and long COVID can arise even after a mild or asymptomatic coronavirus infection. Countries with high infection rates could still end up with many cases of long COVID, even if nations have high rates of vaccination. “That is hard to predict,” says Nisreen Alwan, an epidemiologist at the University of Southampton, UK, who has had long COVID. “We still need to see how much long COVID there is and how long it lasts after vaccination.”

Determining the risk of long COVID from breakthrough infections is challenging. Many people with mild or asymptomatic infections might not be tested for COVID-19, says immunologist Petter Brodin at the Karolinska Institute in Stockholm. “Doing any kind of assessment of how many people develop long-term symptoms after they are vaccinated is going to be incredibly difficult,” he says. “We will miss so many people.”

Residents of Dhaka, Bangladesh wait to get the Covid-19 vaccine from healthcare workers.
People waiting to receive the COVID-19 vaccine in Dhaka, Bangladesh.Credit: Anadolu Agency via Getty

More data should arrive as countries continue to roll out vaccines, including booster shots, and as research funding for studying long COVID is deployed — including more than US$1.1 billion from the US National Institutes of Health (NIH). Long COVID is still a poorly defined syndrome with a wide range of symptoms. A UK study estimates that between 7% and 18% of people who had COVID-19 went on to develop some symptoms of long COVID that lingered for at least 5 weeks3.

For some individuals, long-COVID symptoms are mild; for others, they are life-changing. Nearly one-third of the people with long COVID at Putrino’s clinic have severe cognitive difficulties that can affect their ability to concentrate, speak and remember, and which were not present before their illness. About 60% of Putrino’s patients have had to change jobs or stop working as a result of their illness. “If you’re young and healthy, death from COVID may be highly unlikely,” Putrino says. “But severe debilitation is not.”

The cause of long COVID — also known as the post-acute sequelae of a SARS-CoV-2 infection — is as unclear as its definition. One possibility is that a reservoir of the coronavirus lingers after the acute infection, lurking in various tissues — such as the intestine, liver or brain — and continues to cause damage. Another possibility is that the broad immune response triggered by the initial infection can generate antibodies and other immunological reactions against the body’s own tissues. That could continue to cause complications after the infection has been cleared.

Vaccination could reduce the likelihood of these scenarios. If a vaccine induces high levels of antibodies and T cells capable of recognizing SARS-CoV-2, the immune system could stop the virus during its first few replications before it can establish hidden reservoirs in the body, says Akiko Iwasaki, an immunologist at Yale University in New Haven, Connecticut.

And vaccination allows the body to launch a more-targeted immune response from the moment a coronavirus infiltrates the body, reducing the chance that nonspecific immune reactions will target normal tissue. “The immune system is already sort of pointed in the right direction,” says Brodin. “You’re calling in these very specific cells to attack this specific virus.”

Both anecdotes and data suggest that such protection against long COVID is partial at best, but it is difficult to tease out exactly how common long COVID is in breakthrough infections. One Facebook poll of about 1,950 fully vaccinated people found 44 breakthrough cases, 24 of whom reported long-COVID symptoms. The survey was done by the long-COVID patient-advocacy group Survivor Corps, and the results are reported in a preprint4. But because the poll was not a random sampling of people, the findings cannot be used to estimate the rate of long COVID after vaccination — they show only that such cases exist.

Another study in Israel, of around 1,500 vaccinated health-care workers, found that 7 (19%) of the 39 breakthrough infections produced symptoms that lingered for more than 6 weeks5. However, the numbers of infections studied are too small for firm conclusions to be drawn about the absolute risk.

One of the largest studies so far has gathered data from 1.2 million people who received at least one dose of a COVID-19 vaccine and logged their experience in the COVID Symptom Study app, which was developed by the London-based data-science company ZOE and King’s College London1. The team found that a full two-dose regimen of vaccination reduced the risk of long COVID — as defined by persistent symptoms for at least 28 days after infection — by about half among those who had breakthrough infections. But the study contained disproportionately more women than men and fewer people from lower-income areas.

Still, the message is clear, says Claire Steves, a geriatrician at King’s College London and lead author of the study. Vaccination considerably reduces infection rates and the severity of symptoms: even with waning immunity and the emergence of the more-infectious Delta variant. One study of US veterans found that the COVID-19 vaccines for that group offered about 50% protection against coronavirus infection, even during the Delta surge6. Steves and her colleagues found that vaccination then further reduces the risk of long COVID in those who develop a breakthrough infection by another half: about 11% in the unvaccinated group had persistent symptoms for at least 28 days compared with about 5% in the vaccinated group of breakthrough infections1. Even so, the number of people who developed long COVID from breakthrough infections is significant, she says. “It does still exist — we do still have to be aware that’s the case.”

A COVID-19 vaccination center inside the GUM luxury department store in Moscow, Russia.
A COVID-19 vaccination centre inside a department store in Moscow, Russia.Credit: Andrey Rudakov/Bloomberg via Getty

Another large study2 — which has not yet been peer reviewed — suggests that the situation could be worse: a retrospective analysis of electronic health records from about 10,000 people with breakthrough infections found vaccination did not protect against several conditions associated with long COVID. That group was compared with a control group of people with confirmed SARS-CoV-2 infections who had not been vaccinated against COVID-19, but who had received an influenza vaccine. Differences in how the two studies were designed could account for the different results generated by this work and the COVID Symptom Study, says Maxime Taquet, a psychiatrist and researcher at the University of Oxford, UK, who is first author of the health-records analysis2. For example, Taquet’s study tried to account for potential lifestyle differences between those who received the COVID-19 vaccine and those who did not by including the control group. However, because his study relied on health records, it might not include data for people with milder symptoms that would not have warranted a consultation with a physician.

Overall, Iwasaki has found the results of these studies disappointing. “I honestly thought the vaccine would protect against long COVID much more extensively,” she says. Iwasaki proposes that Delta — which is more transmissible than other variants are — might have weakened the vaccines’ protection against long COVID. If people infected with Delta breathe out a great number of infectious particles, as is thought, the infections that they pass on will have higher initial amounts of virus. That could allow Delta to replicate more readily than other variants, even in fully vaccinated people, says Iwasaki. This higher dose could give the virus a better opportunity to establish a reservoir or provoke an overactive immune response, either of which might then lead to long COVID, she suggests.

As vaccination programmes continue, researchers will gain a better sense of how vaccines and variants affect long-COVID rates and severity. It’s also possible that vaccination might help to reduce long COVID in those who already have the condition. In October, the UK Office for National Statistics, which is collecting data on long COVID, reported that the first dose of a COVID-19 vaccine was associated with a 13% decrease in self-reported long-COVID symptoms among those who already had the condition. The second dose yielded a further 9% drop relative to the first7.

The study followed people for only about two months, so it’s unclear how long the effects will last, says Iwasaki, who has been studying how vaccination affects long-COVID symptoms. But it is largely in line with other findings, she adds. One survey conducted by Survivor Corps found that about 40% of respondents with long COVID reported an improvement in their symptoms after vaccination. Another 14%, however, said that their symptoms got worse8.

The US Centers for Disease Control and Prevention is not tracking mild COVID-19 breakthrough illnesses, and so might miss many cases that lead to long COVID. However, last December, the US Congress allocated the NIH $1.15 billion over 4 years to study the long-term health consequences of SARS-CoV-2 infections; in June, the NIH granted the first awards for a long-COVID research programme called RECOVER. This aims to enrol tens of thousands of people — including those with or without long COVID after acute coronavirus infection, and those who have not been infected — and track their symptoms. One of the main goals is to learn more about the pathology of long COVID and to better define the condition.

Over the course of that study, the RECOVER team should also be able to generate data on rates of long COVID among those who are vaccinated. Other useful information should include the severity, duration and nature of a person’s symptoms and, when possible, the coronavirus variant responsible for their illness, says cardiologist Stuart Katz at New York University, a lead investigator on the programme who has also experienced long COVID. “We are enrolling people and recording the history of vaccination,” says Katz. “But, of course, a big challenge for any research in this space is that we don’t yet really have a definition of what long COVID is.”

The team hopes to finish enrolment in the programme’s first year — a speedy pace for such a large initiative, but still painfully slow given the pressing need to improve treatments for long COVID, says Iwasaki.

RECOVER will also collect data on vaccinated children and adolescents — an important gap in currently published studies, and one that will be easier to fill as vaccines are rolled out to young people in several countries. One study9 of more than 6,700 adolescents found that about 30% of those who tested positive for SARS-CoV-2 had 3 or more symptoms 3 months after diagnosis, compared with 16% of those in a control group that tested negative. The findings from the control group, a factor not included in most other such studies in this age group, bring the rate of long COVID down below some other estimates for adolescents, but means that it is still comparable to the rate seen in adults, says paediatrician Terence Stephenson at University College London. “It’s not the tsunami that perhaps was envisaged,” he says. “But neither is it trivial.”

And while the data trickle in, Alwan worries that countries with high vaccine coverage will put COVID-19 testing on the back burner as concerns about hospitalizations and deaths decrease and as more people receive boosters. That not only hurts efforts to determine the influence of vaccination on long COVID, but also means that those with long COVID after a mild or asymptomatic infection might not have the documentation they need for treatment. “It’s important to get that lab confirmation for care,” she says. “Otherwise, people struggle a lot.”

Heavily mutated coronavirus variant puts scientists on alert

Researchers are racing to determine whether a fast-spreading variant in South Africa poses a threat to COVID vaccines’ effectiveness.

(Update 11/26/2021)

Researchers in South Africa are racing to track the concerning rise of a new variant of the SARS-CoV-2 coronavirus that causes COVID-19. The variant harbours a large number of the mutations found in other variants, including Delta, and it seems to be spreading quickly across South Africa.

A top priority is to follow the variant more closely as it spreads: it was first identified in Botswana earlier this month and has since turned up in a traveller arriving in Hong Kong from South Africa. Scientists are also trying to understand the variant’s properties, such as whether it can evade immune responses triggered by vaccines and whether it causes more or less severe disease than other variants do.

“We’re flying at warp speed,” says Penny Moore, a virologist at the University of the Witwatersrand in Johannesburg, South Africa, whose lab is gauging the variant’s potential to dodge immunity from vaccines and previous infections. There are anecdotal reports of reinfections and of cases in vaccinated individuals, but “at this stage it’s too early to tell anything”, Moore adds.

“There’s a lot we don’t understand about this variant,” Richard Lessells, an infectious-diseases physician at the University of KwaZulu-Natal in Durban, South Africa, said at a press briefing organized by South Africa’s health department on 25 November. “The mutation profile gives us concern, but now we need to do the work to understand the significance of this variant and what it means for the response to the pandemic.”

A World Health Organization (WHO) expert group will meet on 26 November, and will probably label the strain — currently known as B.1.1.529 — as a variant of concern or variant of interest, Tulio de Oliveira, a bioinformatician at the University of KwaZulu-Natal, said at the briefing. The variant will probably be named Nu — the next available letter in the Greek alphabet naming system for coronavirus variants — if it is flagged by the WHO group.

Researchers also want to measure the variant’s potential to spread globally — possibly sparking new waves of infection or exacerbating ongoing rises being driven by Delta.

Changes to spike

Researchers spotted B.1.1.529 in genome-sequencing data from Botswana. The variant stood out because it contains more than 30 changes to the spike protein — the SARS-CoV-2 protein that recognizes host cells and is the main target of the body’s immune responses. Many of the changes have been found in variants such as Delta and Alpha, and are linked to heightened infectivity and the ability to evade infection-blocking antibodies.

The apparent sharp rise in cases of the variant in South Africa’s Gauteng province — home to Johannesburg — is also setting off alarm bells. Cases increased rapidly in the province in November, particularly in schools and among young people, according to Lessells. Genome sequencing and other genetic analysis from de Oliveira’s team found that the B.1.1.529 variant was responsible for all 77 of the virus samples they analysed from Gauteng, collected between 12 and 20 November. Analysis of hundreds more samples are in the works.

The variant harbours a spike mutation that allows it to be detected by genotyping tests that deliver results much more rapidly than genome sequencing does, Lessells said. Preliminary evidence from these tests suggest that B.1.1.529 has spread considerably further than Gauteng. “It gives us concern that this variant may already be circulating quite widely in the country,” Lessells said.

Vaccine effectiveness

To understand the threat B.1.1.529 poses, researchers will be closely tracking its spread in South Africa and beyond. Researchers in South Africa mobilized efforts to quickly study the Beta variant, identified there in late 2020, and a similar effort is starting to study B.1.1.529.

Moore’s team — which provided some of the first data on Beta’s ability to dodge immunity — has already begun work on B.1.1.529. They plan to test the virus’s ability to evade infection-blocking antibodies, as well as other immune responses. The variant harbours a high number of mutations in regions of the spike protein that antibodies recognize, potentially dampening their potency. “Many mutations we know are problematic, but many more look like they are likely contributing to further evasion,” says Moore. There are even hints from computer modelling that B.1.1.529 could dodge immunity conferred by another component of the immune system called T cells, says Moore. Her team hopes to have its first results in two weeks.

“A burning question is ‘does it reduce vaccine effectiveness, because it has so many changes?’,” says Aris Katzourakis, who studies virus evolution at the University of Oxford, UK. Moore says breakthrough infections have been reported in South Africa among people who have received any of the three kinds of vaccines in use there, from Johnson & Johnson, Pfizer–BioNTech and Oxford–AstraZeneca. Two quarantined travellers in Hong Kong who have tested positive for the variant were vaccinated with the Pfizer jab, according to news reports. One individual had travelled from South Africa; the other was infected during hotel quarantining.

Researchers in South Africa will also study whether B.1.1.529 causes disease that is more severe or milder than that produced by other variants, Lessells said. “The really key question comes around disease severity.”

So far, the threat B.1.1.529 poses beyond South Africa is far from clear, researchers say. It is also unclear whether the variant is more transmissible than Delta, says Moore, because there are currently low numbers of COVID-19 cases in South Africa. “We’re in a lull,” she says. Katzourakis says that countries where Delta is highly prevalent should be watching for signs of B.1.1.529. “We need to see what this virus does in terms of competitive success and whether it will increase in prevalence.”

The Covid Response Has Broken Our Trust in American Institutions

(Update 12/03/2021)

 We are coming toward the end of the SARS2 coronavirus pandemic. Deaths are not likely to rise dramatically when cases sharply increase, a different pattern than in the initial waves. That “decoupling” between cases and deaths would be to a great extent due to the successful vaccination of those at risk to die, as well as acquired natural immunity. Unfortunately, it is unlikely the recurring hysteria and mismanagement by those in power will end so quickly.

After more than eighteen months of experience, there remains an almost bizarre lack of understanding that the virus will not simply disappear. Instead, on its way to becoming endemic, cases will continue to peak and ebb periodically, as they have done and continue to do in characteristic cycles all over the world and regionally in the United States. We must learn to live with the virus by offering vaccines to the vulnerable, aggressively exploring early treatments, while also accepting some risk, rather than employing failed, harmful restrictions on low-risk people every time the pattern recurs. Instead of recognizing the evidence, the flow of misleading information lacking perspective, policies counter to scientific data, and the absence of transparency continue.

The unscientific obsession with stopping all cases of COVID-19 continues, including the variants that all scientists expected as the virus mutates and becomes less lethal, without acknowledging the low risk for the overwhelming majority and what should be today’s protection of the most vulnerable to death.

Accountability remains absent from government leaders, public health officials, and scientists in failing to admit errors about lockdowns; some even distort their records and portray disastrous death tallies as “successes.” And now we witness an Orwellian attempt by those who advised what was widely implemented — lockdowns — to blame those who opposed lockdowns for the failure of the lockdowns.

The CDC and public health leaders still fail to visibly acknowledge and then educate the public about the natural immunity in recovered COVID patients or to incorporate that biological fact into our nation’s vaccine policies. The public needs to know that data continues to accrue showing natural immunity after SARS2 infection, like other infectious diseases, is probably superior to vaccine-related protection.

Public health officials and government leaders keep using wildly incorrect projections that instill fear and alarm the public, and when they’re wrong, they fail to acknowledge this fact.

Our public health recommendations did not change after scientific data showed previous rules were arbitrary, incorrect, and ineffective. The six-foot guidelines were not revisited despite the evidence. Many schools force children to wear masks, contrary to science and simple logic. Must we prove the earth is round again?

Serious problems with the data, including misleading PCR testing and overcounting of COVID as the cause of many hospitalizations and deaths in the United States, have never been explained to the public and acknowledged, even though it has been documented in the medical literature.

There continue to be delays in clinical trials and approvals of safe, widely available drugs that show potential efficacy in clinical reports, as if vaccination is the only option.

A COVID testing requirement has been imposed in schools and university campuses, grossly violating ethical standards, including the CDC’s own statement only months ago published in late 2020 that “it is both unethical and illegal to test someone who doesn’t want to be tested, including students whose parents or guardians do not want them to be tested.”

The spirit if not the letter of informed consent has been violated with a vaccine clinical trial in young, healthy children who have extremely low risk from the illness and rarely spread it.

The nation still awaits any indication that there will be a full investigation into the origin of the deadly virus, even if it uncovers potential corruption in our nation’s top science agencies and public health leaders. The world is owed full exposure of the truth without delay.

Why do these failures persist in a nominally science-based, freethinking, and ethical society like ours? Is the herd mentality so powerful, is fear such a dominant emotion, that all critical thinking and values disappear? If the US tallies 50,000 deaths from COVID next year, will we accept that with the relaxed attitude we have about the flu, which has that death toll every year? If not, why not? Are we a nation of science or science-deniers? Do we demand accountability and learn from past error? Is this country committed to the free exchange of ideas, so that truth is determined by evidence and debate rather than decree and false declarations of consensus? Do facts still matter? And what is the end-point, an endless series of panic-driven lockdowns or finally a recognition that the virus will become endemic? Are we committed to civil liberties? The answers to these questions are profoundly consequential.

One issue stands above all others—the urgent need to restore trust in our vital institutions. The management of this pandemic has left a stain on many of America’s once noble institutions. Earning trust back will not be easy.

Trust in government

Almost all governors made entirely arbitrary distinctions. Even if one believed in the health benefits of these diktats, they were handed down with shocking disregard for the potential damages and deaths. In addition to seeing convincing data to justify such measures in the future, the citizenry must be convinced that rules apply to everyone. When elected officials are caught enjoying indoor dining with lobbyists, or public health leaders ignore their own restrictions on family gatherings, they undermine the moral legitimacy necessary for voluntary compliance. That puts the rule of law in future emergencies at risk.

Trust in public health leadership

There has been a repeated, erratic discussion and a shameful absence of critical thinking coming from public health officials. On masks, America’s leading voice of public health issued a number of statements over a period of months that were in direct conflict with each other and with the data, and he still fails to recognize the most compelling studies. On testing, the CDC put up a guideline, then changed it, then took it down, then put back something close to the original. There was no science to prompt those changes. The most visible face of public health praised four northeast US states with the highest rate of fatalities for following his guidance, despite their deadly performance. We also saw statements, actions, and a lack of transparency from our top health and medical agencies that undermined trust in vaccines and potential treatments, an extremely important part of saving lives in the next pandemic

Trust in science

The pandemic exposed grave problems with the essential functioning of science, research and debate. Elite research universities, public health agencies, and top scientific journals quickly fell in line with herd thinking about the pandemic. Instead of open and free discourse to seek the scientific truths underlying urgently needed solutions, we have seen silencing, censoring, and slandering of scientists whose interpretations differed from the desired narrative. Motivation must be questioned once one realizes that most scientists and academics are highly dependent on the NIH for funding, the key to publications and career advancement.  Prestigious journals are now openly contaminated with politics.  Academia and the research community, dominated by a single viewpoint, actively engage in intimidation and false declarations of consensus, as well as through abuse of the peer-review system. That intolerance has fostered a climate of fear and inhibited other scientists and health experts from contributing to the discussion, effectively inducing self-censorship. This dangerous trend threatens the free exchange of ideas essential to democracy.

Trust in educational leaders

The priorities of teachers and their unions were exposed as self-centered, driven by fear for the adult teachers, most of whom are at very low risk, at the expense of the health and future of children. The same holds true for our university leadership. Children are not to be used as shields for adults in any civilized society. No longer can we, as parents and concerned citizens, permit coerced injections of experimental drugs and required testing for access to university education. These requirements are not only unscientific, they also violate our nation’s long-established standards for ethical conduct, medical privacy, and autonomy over one’s own body.

Trust in fellow citizens

Policymakers in concert with the elite class inflicted great harm by undermining fundamental trust in our fellow citizens. Elites in the media have made “freedom” a selfish idea and politicized dissent on the efficacy of masks or various potential treatments. Restrictions on liberty were also destructive by inflaming class distinctions with their differential impact: exposing essential workers, sacrificing low-income families and kids, destroying single-parent homes, and eviscerating small businesses, while at the same time large companies were bailed out, elites worked from home with barely an interruption, and the ultra-rich got richer, leveraging their bully pulpit to demonize and cancel those who challenged their preferred policy options. We should know who to trust by now.

In considering all the surprising events that unfolded in this past year, two in particular stand out. I have been shocked at the enormous power of government officials to unilaterally decree a sudden and severe shutdown of society—to simply close businesses and schools by edict, restrict personal movements, mandate behavior, regulate interactions with our family members, and eliminate our most basic freedoms, without any defined end and with little accountability. And I remain stunned at the acceptance by the American people of draconian rules, restrictions, and unprecedented mandates, even those that are arbitrary, destructive, and wholly unscientific. The acquiescence of the citizenry to such extraordinary and ill-conceived restrictions in a nation that was founded on the principles of freedom from an overbearing government, in a country that stands as the world’s beacon for independence and liberty, is nothing less than shocking.

Today, after all that we have endured from this pandemic, we still must ask why so few were willing to speak out when the most disastrous health policies in history were foisted on ordinary people and above all on our children, our country’s most precious resource. Where were the scientists? The economists? The pediatricians and psychologists? The teachers and university leaders? The constitutional lawyers? The human rights advocates? The ethicists?

This crisis has also exposed what we all know has existed for years but have tolerated in this country—the overt bias of the media, the lack of diverse viewpoints on campuses, the absence of neutrality in controlling social media, and now more visibly than ever the intrusion of politics into science. Ultimately, the freedom to seek the truth and openly state it is at risk.

The United States is on the precipice of losing its cherished freedoms, with censorship and cancellation of all those who bring views forward that differ from the “accepted mainstream.” It is not clear if our democracy, with its defining freedoms, will fully recover, even after we survive the pandemic itself. But it is clear that people must step up—meaning speak up, as we are allowed, as we are expected to do in free societies—or it has no chance.

In 1841, Charles Mackay presciently spoke about the herd mentality: “Men, it has been well said, think in herds; it will be seen that they go mad in herds, while they only recover their senses slowly, and one by one.” So how do we proceed at this very moment, in this country, with its heavily damaged psyche? Those of us who want the truth must keep seeking it, and those of us who see the truth must keep speaking it. Because truth matters.

covid-19 and Healthcare Postings