It has finally happened, My flagship postings on the Coronavirus have reached a critical mass, and I will no longer be able to update them any longer. So I will now start a part three to continue on with general articles on the virus. You will can still refer back to those parts, there is a lot of good information on the virus, including the anatomy and physiology of the human body and how viruses attack and affect the body. So please feel free to refer back to them for reference. You may have noticed that over the last several months I have added three more postings on the virus, that I have been routinely updating, one on masks https://common-sense-in-america.com/2022/03/26/mask-or-no-mask-for-covid-19/ ; another on vaccines https://common-sense-in-america.com/2022/03/12/the-covid-19-vaccine-safe-or-unsafe/ and a third one on the various variants of the virus https://common-sense-in-america.com/2022/02/27/the-skinny-on-covid-19-variants/. I will continue to update them as new information surfaces or comes to light.
Table of Contents
-The four most urgent questions about long COVID
-The lasting misery of coronavirus long-haulers
-Profile of a killer: the complex biology powering the coronavirus pandemic
-Mysterious wave of COVID toes still has scientists stumped
-Why the WHO took two years to say COVID is airborne
-Are some people resistant to COVID-19? Geneticists are on the hunt
-Even mild COVID-19 can cause your brain to shrink
-Has The CDC Been Truthful About The Mental Health Impact Of Lockdowns?
-COVID is spreading in deer. What does that mean for the pandemic?
-Where did Omicron come from? Three key theories
-CDC Tracked Phones To Check If Americans Followed Lockdown Orders
-Covid: World’s true pandemic death toll nearly 15 million, says WHO
-Flu vaccine could cut COVID risk
-How long does COVID-19 linger in your body? New report offers clues.
-Viruses that were on hiatus during Covid are back — and behaving in unexpected ways
-COVID and smell loss: answers begin to emerge
-COVID antibody drugs have saved lives — so why aren’t they more popular?
The four most urgent questions about long COVID
Scientists are starting to get insights into the lingering disorder that affects some people infected with SARS-CoV-2 — but many mysteries remain unsolved.
When Claire Hastie fell ill in March of last year, she reacted the way she usually would to a minor ailment: she tried to ignore it. “It started off incredibly mild,” she says. “I would normally have paid no attention to it whatsoever.”
But within a week she was flattened. “I had just never felt ill in this way before. I felt like I had an elephant sitting on my chest.” At times, she became convinced she was going to die.
A single mother of three, Hastie “said what I thought might be my final words to the one child who happened to be walking past my bedroom door”. Although her condition is not quite as overwhelming one year on, she says, “I’ve never had a symptom-free day since.”
Hastie has what is now called long COVID: a long-lasting disorder that arises following infection with SARS-CoV-2, the virus that causes COVID-19.
Surveys of thousands of people have revealed an extensive list of symptoms, such as fatigue, dry cough, shortness of breath, headaches and muscle aches. A team led by Athena Akrami, a neuroscientist at University College London who has long COVID, found 205 symptoms in a study of more than 3,500 people. By month 6, the most common were “fatigue, post-exertional malaise, and cognitive dysfunction”. These symptoms fluctuate, and people often go through phases of feeling better before relapsing.
In the first months of the pandemic, the idea that the virus might cause a chronic condition was overlooked in the desperate struggle to deal with acute cases. But Hastie soon realized that she was not alone in having a lingering form of the disease. In May 2020, she started a Facebook group for people with long COVID. Today, it has more than 40,000 members and works with research groups studying the condition — with Hastie sometimes appearing as a co-author of papers.
Meanwhile, long COVID has moved from a curiosity, dismissed by many, to a recognized public-health problem. In January, the World Health Organization revised its guidelines for COVID-19 treatment to include a recommendation that all patients should have access to follow-up care in case of long COVID.
Funding agencies are also paying attention. On 23 February, the US National Institutes of Health (NIH) announced that it would spend US$1.15 billion over four years into research on long COVID, which it refers to as “post-acute sequelae of COVID-19 (PASC)”. In the United Kingdom, the National Institute for Health Research (NIHR) announced in February that it was investing £18.5 million (US$25.8 million) to fund four studies of long COVID — and the following month, it launched another round of funding worth £20 million. The UK BioBank plans to send self-testing kits to all its 500,000 participants, so that those with SARS-CoV-2 antibodies can be identified and invited for further studies.
As the number of confirmed COVID cases tops 170 million across the globe, millions of people might be experiencing persistent symptoms and searching for answers about their future health. Here, Nature looks at four of the biggest questions that scientists are investigating about the mysterious condition known as long COVID.
How many people get long COVID and who is most at risk?
There is increasing clarity on the overall prevalence of long COVID, thanks to a series of surveys — but it is less certain who is most at risk, and why it affects only some.
Most of the early prevalence studies looked only at people who had been hospitalized with acute COVID-19. Ani Nalbandian, a cardiologist at Columbia University Irving Medical Center in New York, and her colleagues collated nine such studies for a review published on 22 March. They found that between 32.6% and 87.4% of patients reported at least one symptom persisting after several months.
But most people with COVID-19 are never ill enough to be hospitalized. The best way to assess the prevalence of long COVID is to follow a representative group of people who have tested positive for the virus. The UK Office of National Statistics (ONS) has done just that, by following more than 20,000 people who have tested positive since April 2020 (see ‘Uncertain endpoint’). In its most recent analyses, published on 1 April, the ONS found that 13.7% still reported symptoms after at least 12 weeks (there is no widely agreed definition of long COVID, but the ONS considers it to be COVID-19 symptoms that last more than 4 weeks).
“I think that’s the best estimate so far,” says Akrami, who now splits her research time between her original focus, neuroscience, and work on long COVID.
In other words, more than one in 10 people who became infected with SARS-CoV-2 have gone on to get long COVID. If the UK prevalence is applicable elsewhere, that’s more than 16 million people worldwide.
The condition seems to be more common in women than in men. In another ONS analysis, 23% of women and 19% of men still had symptoms 5 weeks after infection. That is “striking”, says Rachael Evans, a clinician scientist at the University of Leicester, UK, and a member of the Post-Hospitalization COVID-19 study (PHOSP-COVID). “If you’re male and get COVID, you’re more likely to go to hospital and you’re more likely to die. Yet if you survive, actually it’s females that are much more likely to get the ongoing symptoms.”
There is also a distinctive age distribution. According to the ONS, long COVID is most common in middle-aged people: the prevalence was 25.6% at 5 weeks for those between 35 and 49 years old. It is less common in younger people and older people — although Evans says the latter finding is probably due to ‘survivor bias’, because so many old people who have had COVID-19 have died.
And although long COVID is rarer in younger people, that does not mean it is absent. Even for children aged 2–11, the ONS estimates that 9.8% of those who test positive for the virus still have symptoms after at least 5 weeks, reinforcing the suggestion from other studies that children can get long COVID. Yet some medical professionals play down the idea, says Sammie Mcfarland, who founded the UK-based support group Long Covid Kids. “Long COVID in children isn’t believed. The symptoms are minimized.”
Nevertheless, age and sex are surprisingly powerful for identifying people at risk. A paper published in March presented a model that successfully predicted whether a person would get long COVID using only their age, their sex and the number of symptoms reported in the first week.
Still, many uncertainties remain. In particular, if about 10% of people infected with SARS-CoV-2 get long COVID — as the ONS data suggest — why those 10%?
What is the underlying biology of long COVID?
Although researchers have exhaustively surveyed the diverse symptoms of long COVID, no clear explanation for them exists. “We need people to be looking at the mechanisms,” says Hastie. This will not be easy: studies have shown that many people with long COVID have problems with multiple organs, suggesting that it is a multisystem disorder.
It seems unlikely that the virus itself is still at work, says Evans. “Most of the studies have shown that after a few weeks you’ve pretty much cleared it, so I very much doubt it’s an infective consequence.”
However, there is evidence that fragments of the virus, such as protein molecules, can persist for months, in which case they might disrupt the body in some way even if they cannot infect cells.
A further possibility is that long COVID is caused by the immune system going haywire and attacking the rest of the body. In other words, long COVID could be an autoimmune disease. “SARS-CoV-2 is like a nuclear bomb in terms of the immune system,” says Steven Deeks, a physician and infectious-disease researcher at the University of California, San Francisco. “It just blows everything up.” Some of those changes might linger — as has been seen in the aftermath of other viral infections (see ‘What is the relationship between long COVID and other post-infection syndromes?’).
Still, it is too early to say which hypothesis is correct, and it might be that each is true in different people: preliminary data suggest that long COVID could be several disorders lumped into one.
Some researchers are taking that next step, hoping to unpick the biology. PHOSP-COVID has recruited more than 1,000 UK patients and taken blood samples to look for evidence of inflammation, cardiovascular problems and other changes. Similarly, Deeks has helped to recruit almost 300 COVID-19 patients who have since been followed up every 4 months and have given blood and saliva samples. “We have a massive specimen bank,” says Deeks. “We’re looking at inflammatory outcomes, changes in the coagulation system, evidence that the virus persists.” The team has found altered levels of cytokines — molecules that help to regulate immune responses — in the blood of people who have had COVID-19, suggesting that the immune system is indeed out of balance, as well as protein markers suggesting neuronal dysfunction.
A better understanding of the underlying biology will point the way to treatments and medications, says Evans. But it seems unlikely that there is a single, neat explanation for long COVID. Most researchers now suspect several mechanisms are at work, so one person’s long COVID might be profoundly different from another’s. In October, a review published by the NIHR raised the possibility that long COVID symptoms “may be due to a number of different syndromes”. “There is a story emerging,” says Deeks. “There’s not one clinical phenotype. There’s different flavors, different clusters. They all may have different mechanisms.” His group plans to use machine learning to work out how many types there are and how they differ.
Evans and her PHOSP-COVID colleagues have taken a stab at this, in a preprint posted on 25 March. They studied 1,077 COVID-19 patients, recording symptoms including physical impairments, mental-health difficulties such as anxiety, and cognitive impairments in areas such as memory and language. The researchers also recorded basic information such as age and sex, and biochemical data such as levels of C-reactive protein — a measure of inflammation. The team then used a mathematical tool called cluster analysis to see whether there were identifiable groups of patients with similar profiles.
“We would think if you had a terrible acute lung injury and multi-organ failure, those would be the people that would have the ongoing pathology,” says Evans. But the study found little relationship between the severity of the acute phase, or levels of organ damage, and the severity of long COVID.
The reality was more complicated. The analysis identified four clusters of long COVID patients whose symptoms were distinct. Three of the groups had mental-health and physical impairments to varying degrees, but few or no cognitive difficulties. The fourth cluster showed only moderate mental-health and physical impairments, but had pronounced cognitive problems.
“Cognition was really quite separate, and we weren’t expecting that,” says Evans. She emphasizes that the study does not unpick the underlying mechanisms. “But it is definitely a first step.”
What is the relationship between long COVID and other post-infection syndromes?
Some scientists weren’t surprised by long COVID. Illnesses that linger after an infection have been reported in the scientific literature for 100 years, says Anthony Komaroff, an internal-medicine physician at Harvard Medical School in Boston, Massachusetts.
He noted that fact in March, during a webinar organized by MEAction, an organization based in Santa Monica, California, that works to raise awareness of myalgic encephalitis, also known as chronic fatigue syndrome (ME/CFS). People with this debilitating illness become exhausted after even mild activity, alongside experiencing other symptoms such as headaches. Long dismissed by some medical professionals because it had no clear biological underpinning, ME/CFS is often post-viral.
It isn’t uncommon for an infection to trigger long-lasting symptoms. One study of 253 people diagnosed with certain viral or bacterial infections found that after 6 months, 12% reported persistent symptoms including “disabling fatigue, musculoskeletal pain, neurocognitive difficulties, and mood disturbance”. That percentage is strikingly similar to the long COVID prevalence observed in the United Kingdom by the ONS.
Some people with long COVID will probably meet the diagnostic criteria for ME/CFS, according to Komaroff and his colleague Lucinda Bateman, founder of the Bateman Horne Center in Salt Lake City, Utah, which specializes in treating ME/CFS. But there do seem to be differences: for instance, people with long COVID are more likely to report shortness of breath than are those with ME/CFS, Komaroff says. Furthermore, if long COVID does end up being subdivided into multiple syndromes, that will further complicate comparisons between it and ME/CFS.
“I’ve so far resisted saying long COVID is ME/CFS, because I really think it is an umbrella term and there are multiple things happening in this long COVID umbrella,” says Nisreen Alwan, a public-health researcher at the University of Southampton, UK. And Deeks speaks for many: “I think everybody needs to be a bit agnostic now, and not make too many assumptions, and not put all these different syndromes into the same bucket.” What many do agree on, however, is that the two conditions could productively be studied in tandem. “There should be a coalition,” says Alwan. Some researchers are already planning to collaborate. For instance, a major study called DecodeME aims to recruit 20,000 people to find genetic factors that contribute to ME/CFS — and Evans says PHOSP-COVID will be sharing data with it.
“I’m really hopeful that the silver lining will be, at the end of the day, we gain better insight into other post-viral problems,” says Akrami.
Hastie puts it more bluntly: “Let’s not waste a good crisis.”
What can be done to help people with long COVID?
Right now, the options are fairly limited, because the disorder is so poorly understood.
Some countries are opening clinics for people with long COVID. In Germany, a company called MEDIAN has begun accepting people with long COVID at some of its private rehabilitation clinics. In England, the National Health Service has provided £10 million for a network of 69 clinics: these have started to assess and help people with the condition.
That is a welcome first step, says Hastie, but few evidence-based treatments exist. There is a growing consensus that multidisciplinary teams are needed, because long COVID affects so many parts of the body. “Every person on average has, like, 16 or 17 symptoms,” says Akrami. Often the clinics do not have such teams.
Much of the challenge will be social and political, because people with long COVID must rest, often for months at a time, and they need support while they do so. Their conditions “need to be recognized as a disability”, says Hastie.
In terms of medicines, a handful are being tested. Biotechnology company PureTech Health in Boston, Massachusetts, announced in December that it was starting a clinical trial of deupirfenidone, an anti-fibrotic and anti-inflammatory agent that it has developed. Results are expected in the second half of 2021. In the United Kingdom, intensive-care specialist Charlotte Summers at the University of Cambridge and her colleagues have launched a study called HEAL-COVID, which aims to prevent long COVID from taking hold. Participants who have been hospitalized with COVID-19 will be given one of two drugs after being discharged: apixaban, an anticoagulant that might reduce the risk of dangerous blood clots; and atorvastatin, an anti-inflammatory. In the United States, the NIH is funding a trial of existing drugs that people with mild COVID-19 can administer at home. Participants will be followed for 90 days to test the drugs’ impact on longer-term symptoms.
Finally, there is the question of what part COVID-19 vaccines might play. Although many of them prevent death and severe illness, scientists do not yet know whether they prevent long COVID.
What about the impact of vaccines in people who already have long COVID? A UK survey of more than 800 people with long COVID, which has not been peer reviewed, reported in May that 57% saw an overall improvement in their symptoms, 24% no change and 19% a deterioration after their first dose of vaccine. In April, Akrami’s team launched a systematic survey to shed more light. “People need to get vaccinated to come out of the pandemic, but we need to first address their concern of whether the vaccine is going to help, or not harm, or [be] harmful.”
Similarly, Akiko Iwasaki, an immuno-biologist at Yale University in New Haven, Connecticut, is recruiting people with long COVID who have not been vaccinated, so she and her colleagues can track how their bodies react to the vaccine. She hypothesizes that the vaccine might improve symptoms by eliminating any virus or viral remnants left in the body, or by rebalancing the immune system.
People with long COVID just want something that works. “How can we get better?” asks Hastie. “That’s what we want to know.”
The lasting misery of coronavirus long-haulers
Months after infection with SARS-CoV-2, some people are still battling crushing fatigue, lung damage and other symptoms of ‘long COVID’.
The lung scans were the first sign of trouble. In the early weeks of the coronavirus pandemic, clinical radiologist Ali Gholamrezanezhad began to notice that some people who had cleared their COVID-19 infection still had distinct signs of damage. “Unfortunately, sometimes the scar never goes away,” he says.
Gholamrezanezhad, at the University of Southern California in Los Angeles, and his team started tracking patients in January using computed tomography (CT) scanning to study their lungs. They followed up on 33 of them more than a month later, and their as-yet-unpublished data suggest that more than one-third had tissue death that has led to visible scars. The team plans to follow the group for several years.
These patients are likely to represent the worst-case scenario. Because most infected people do not end up in hospital, Gholamrezanezhad says the overall rate of such intermediate-term lung damage is likely to be much lower — his best guess is that it is less than 10%. Nevertheless, given that 28.2 million people are known to have been infected so far, and that the lungs are just one of the places that clinicians have detected damage, even that low percentage implies that hundreds of thousands of people are experiencing lasting health consequences.
Doctors are now concerned that the pandemic will lead to a significant surge of people battling lasting illnesses and disabilities. Because the disease is so new, no one knows yet what the long-term impacts will be. Some of the damage is likely to be a side effect of intensive treatments such as intubation, whereas other lingering problems could be caused by the virus itself. But preliminary studies and existing research into other coronaviruses suggest that the virus can injure multiple organs and cause some surprising symptoms.
People with more severe infections might experience long-term damage not just in their lungs, but in their heart, immune system, brain and elsewhere. Evidence from previous coronavirus outbreaks, especially the severe acute respiratory syndrome (SARS) epidemic, suggests that these effects can last for years.
And although in some cases the most severe infections also cause the worst long-term impacts, even mild cases can have life-changing effects — notably a lingering malaise similar to chronic fatigue syndrome.
Many researchers are now launching follow-up studies of people who had been infected with SARS-CoV-2, the virus that causes COVID-19. Several of these focus on damage to specific organs or systems; others plan to track a range of effects. In the United Kingdom, the Post-Hospitalization COVID-19 Study (PHOSP-COVID) aims to follow 10,000 patients for a year, analyzing clinical factors such as blood tests and scans, and collecting data on biomarkers. A similar study of hundreds of people over 2 years launched in the United States at the end of July.
What they find will be crucial in treating those with lasting symptoms and trying to prevent new infections from lingering. “We need clinical guidelines on what this care of survivors of COVID-19 should look like,” says Nahid Bhadelia, an infectious-diseases clinician at Boston University School of Medicine in Massachusetts, who is setting up a clinic to support people with COVID-19. “That can’t evolve until we quantify the problem.”
In the first few months of the pandemic, as governments scrambled to stem the spread by implementing lockdowns and hospitals struggled to cope with the tide of cases, most research focused on treating or preventing infection.
Doctors were well aware that viral infections could lead to chronic illness, but exploring that was not a priority. “At the beginning, everything was acute, and now we’re recognizing that there may be more problems,” says Helen Su, an immunologist at the National Institute of Allergy and Infectious Diseases in Bethesda, Maryland. “There is a definite need for long-term studies.”
The obvious place to check for long-term harm is in the lungs, because COVID-19 begins as a respiratory infection. Few peer-reviewed studies exploring lasting lung damage have been published. Gholamrezanezhad’s team analyzed lung CT images of 919 patients from published studies1, and found that the lower lobes of the lungs are the most frequently damaged. The scans were riddled with opaque patches that indicate inflammation, that might make it difficult to breathe during sustained exercise. Visible damage normally reduced after two weeks. An Austrian study also found that lung damage lessened with time: 88% of participants had visible damage 6 weeks after being discharged from hospital, but by 12 weeks, this number had fallen to 56.
Symptoms might take a long time to fade; a study posted on the preprint server medRxiv in August followed up on people who had been hospitalized, and found that even a month after being discharged, more than 70% were reporting shortness of breath and 13.5% were still using oxygen at home.
Evidence from people infected with other coronaviruses suggests that the damage will linger for some. A study published in February recorded long-term lung harm from SARS, which is caused by SARS-CoV-1. Between 2003 and 2018, Peixun Zhang at Peking University People’s Hospital in Beijing and his colleagues tracked the health of 71 people who had been hospitalized with SARS. Even after 15 years, 4.6% still had visible lesions on their lungs, and 38% had reduced diffusion capacity, meaning that their lungs were poor at transferring oxygen into the blood and removing carbon dioxide from it.
COVID-19 often strikes the lungs first, but it is not simply a respiratory disease, and in many people, the lungs are not the worst-affected organ. In part, that’s because cells in many different locations harbor the ACE2 receptor that is the virus’s major target, but also because the infection can harm the immune system, which pervades the whole body.
Some people who have recovered from COVID-19 could be left with a weakened immune system. Many other viruses are thought to do this. “For a long time, it’s been suggested that people who have been infected with measles are immunosuppressed in an extended period and are vulnerable to other infections,” says Daniel Chertow, who studies emerging pathogens at the National Institutes of Health Clinical Center in Bethesda, Maryland. “I’m not saying that would be the case for COVID, I’m just saying there’s a lot we don’t know.” SARS, for instance, is known to decrease immune-system activity by reducing the production of signaling molecules called interferons.
Su and her colleagues hope to enroll thousands of people worldwide in a project called the COVID Human Genetic Effort, which aims to find genetic variants that compromise people’s immune systems and make them more vulnerable to the virus. They plan to expand the study to those with long-term impairment, hoping to understand why their symptoms persist and to find ways to help them. “Someone who has prolonged problems, beyond what would be normally seen, they would be of interest to study,” says Su.
The virus can also have the opposite effect, causing parts of the immune system to become overactive and trigger harmful inflammation throughout the body. This is well documented in the acute phase of the illness, and is implicated in some of the short-term impacts. For instance, it might explain why a small number of children with COVID-19 develop widespread inflammation and organ problems.
This immune over-reaction can also happen in adults with severe COVID-19, and researchers want to know more about the knock-on effects after the virus has run its course. “It seems there’s a lag there for it to get hold of the person and then cause this severe inflammation,” says Adrienne Randolph, a senior associate in critical-care medicine at Boston Children’s Hospital. “But then the thing is that, long term, when they recover, how long does it take the immune system to settle back to normality?”
Heart of the matter
An over-reactive immune system can lead to inflammation, and one particularly susceptible organ is the heart. During the acute phase of COVID-19, about one-third of patients show cardiovascular symptoms, says Mao Chen, a cardiologist at Sichuan University in Chengdu, China. “It’s absolutely one of the short-term consequences.”
One such symptom is cardiomyopathy, in which the muscles of the heart become stretched, stiff or thickened, affecting the heart’s ability to pump blood. Some patients also have pulmonary thrombosis, in which a clot blocks a blood vessel in the lungs. The virus can also injure the wider circulatory system, for instance, by infecting the cells lining blood vessels.
“My major concern is also the long-term impact,” says Chen. In some patients, he says, the risk to the cardiovascular system “lingers for a long time”. Chen and his colleagues reviewed data from before the pandemic for a study published in May, noting that people who have had pneumonia are at increased risk of cardiovascular disease 10 years later — although the absolute risk is still small. Chen speculates that an over-reactive immune system, and the resulting inflammation, might be involved. However, there is little information on long-term cardiovascular harms from SARS or the related disease Middle Eastern respiratory syndrome (MERS), let alone from SARS-CoV-2.
Studies are now starting. At the beginning of June, the British Heart Foundation in London announced six research programs, one of which will follow hospitalized patients for six months, tracking damage to their hearts and other organs. Data-sharing initiatives such as the CAPACITY registry, launched in March, are compiling reports from dozens of European hospitals about people with COVID-19 who have cardiovascular complications.
Similar long-term studies are needed to understand the neurological and psychological consequences of COVID-19. Many people who become severely ill experience neurological complications such as delirium, and there is evidence that cognitive difficulties, including confusion and memory loss, persist for some time after the acute symptoms have cleared. But it is not clear whether this is because the virus can infect the brain, or whether the symptoms are a secondary consequence — perhaps of inflammation.
One of the most insidious long-term effects of COVID-19 is its least understood: severe fatigue. Over the past nine months, an increasing number of people have reported crippling exhaustion and malaise after having the virus. Support groups on sites such as Facebook host thousands of members, who sometimes call themselves “long-haulers”. They struggle to get out of bed, or to work for more than a few minutes or hours at a time. One study of 143 people with COVID-19 discharged from a hospital in Rome found that 53% had reported fatigue and 43% had shortness of breath an average of 2 months after their symptoms started. A study of patients in China showed that 25% had abnormal lung function after 3 months, and that 16% were still fatigued.
Paul Garner, a infectious-disease researcher at the Liverpool School of Tropical Medicine, UK, has experienced this at first hand. His initial symptoms were mild, but he has since experienced “a roller coaster of ill health, extreme emotions and utter exhaustion”. His mind became “foggy” and new symptoms cropped up almost every day, ranging from breathlessness to arthritis in his hands.
These symptoms resemble chronic fatigue syndrome, also known as myalgic encephalomyelitis (ME). The medical profession has struggled for decades to define the disease — leading to a breakdown of trust with some patients. There are no known biomarkers, so it can only be diagnosed based on symptoms. Because the cause is not fully understood, it is unclear how to develop a treatment. Dismissive attitudes from doctors persist, according to some patients.
People reporting chronic fatigue after having COVID-19 describe similar difficulties. In the forums, many long-haulers say they have received little or no support from doctors — perhaps because many of them showed only mild symptoms, or none at all, and were never hospitalized or in danger of dying. It will not be easy to establish the links between COVID-19 and fatigue with certainty, says Randolph. Fatigue does not seem to be limited to severe cases. It is common in people who had mild symptoms and who therefore might not have been tested for the virus.
The only way to find out whether SARS-CoV-2 is behind these symptoms is to compare people known to have had the virus with those who have not, says Chertow, to see how often fatigue manifests and in what form. Otherwise there is a risk of lumping together people whose fatigue has manifested for different reasons, and who might need distinct treatments.
Chertow says he is not aware of such a study for COVID-19, but they have been done for other diseases. Following the Ebola epidemic in West Africa in 2014–16, US researchers collaborated with the Ministry of Health in Liberia to perform a long-term follow-up study called Prevail III. The study identified six long-term impacts from Ebola, ranging from joint pain to memory loss. Bhadelia, who treated hundreds of people with Ebola during the outbreak, says that these post-viral symptoms had not previously been recognized. Usually, she says, “we don’t stick around past the acute stage. We don’t look at the long tail of recovery. It’s important to do that, because it tells you more about the virus and its pathophysiology.”
The situation is clearer for people who have been severely ill with COVID-19, especially those who ended up on ventilators, says Chertow. In the worst cases, patients experience injury to muscles or the nerves that supply them, and often face “a really long-fought battle on the order of months or up to years” to regain their previous health and fitness, he says. He and his colleagues are now recruiting people with COVID-19 from across the severity spectrum for a long-term follow-up study, assessing their brains, lungs, hearts, kidneys and inflammation responses while they are.
Once again, there is evidence from SARS that coronavirus infection can cause long-term fatigue. In 2011, Harvey Moldofsky and John Patcai at the University of Toronto in Canada described 22 people with SARS, all of whom remained unable to work 13–36 months after infection. Compared with matched controls, they had persistent fatigue, muscle pain, depression and disrupted sleep. Another study, published in 2009, tracked people with SARS for 4 years and found that 40% had chronic fatigue. Many were unemployed and had experienced social stigmatization.
It is not clear how viruses might do this damage, but a 2017 review of the literature on chronic fatigue syndrome found that many patients have persistent low-level inflammation, possibly triggered by infection.
If COVID-19 is such a trigger, a wave of psychological effects “may be imminent”, write a group of researchers led by Declan Lyons, a psychiatrist at St Patrick’s Mental Health Services in Dublin13. The ME Association, a UK-based charity, says it has received many reports of previously healthy people whose energy levels have not returned to normal after becoming infected with the virus, and expects to see new cases of chronic fatigue syndrome. In many countries, the pandemic shows no sign of waning, and health systems are already at capacity responding to acute cases. Nevertheless, researchers say it is crucial to start digging into the long-term effects now.
But the answers will not come quickly. “The problem is,” says Gholamrezanezhad, “to assess long-term consequences, the only thing you need is time.”
Profile of a killer: the complex biology powering the coronavirus pandemic
Scientists are piecing together how SARS-CoV-2 operates, where it came from and what it might do next — but pressing questions remain about the source of COVID-19.
In 1912, German veterinarians puzzled over the case of a feverish cat with an enormously swollen belly. That is now thought to be the first reported example of the debilitating power of a coronavirus. Veterinarians didn’t know it at the time, but coronaviruses were also giving chickens bronchitis, and pigs an intestinal disease that killed almost every piglet under two weeks old.
The link between these pathogens remained hidden until the 1960s, when researchers in the United Kingdom and the United States isolated two viruses with crown-like structures causing common colds in humans. Scientists soon noticed that the viruses identified in sick animals had the same bristly structure, studded with spiky protein protrusions. Under electron microscopes, these viruses resembled the solar corona, which led researchers in 1968 to coin the term coronaviruses for the entire group.
It was a family of dynamic killers: dog coronaviruses could harm cats, the cat coronavirus could ravage pig intestines. Researchers thought that coronaviruses caused only mild symptoms in humans, until the outbreak of severe acute respiratory syndrome (SARS) in 2003 revealed how easily these versatile viruses could kill people.
Now, as the death toll from the COVID-19 pandemic surges, researchers are scrambling to uncover as much as possible about the biology of the latest coronavirus, named SARS-CoV-2. A profile of the killer is already emerging. Scientists are learning that the virus has evolved an array of adaptations that make it much more lethal than the other coronaviruses humanity has met so far. Unlike close relatives, SARS-CoV-2 can readily attack human cells at multiple points, with the lungs and the throat being the main targets. Once inside the body, the virus makes use of a diverse arsenal of dangerous molecules. And genetic evidence suggests that it has been hiding out in nature possibly for decades.
But there are many crucial unknowns about this virus, including how exactly it kills, whether it will evolve into something more — or less — lethal and what it can reveal about the next outbreak from the coronavirus family.
“There will be more, either out there already or in the making,” says Andrew Rambaut, who studies viral evolution at the University of Edinburgh, UK.
Of the viruses that attack humans, coronaviruses are big. At 125 nanometers in diameter, they are also relatively large for the viruses that use RNA to replicate, the group that accounts for most newly emerging diseases. But coronaviruses really stand out for their genomes. With 30,000 genetic bases, coronaviruses have the largest genomes of all RNA viruses. Their genomes are more than three times as big as those of HIV and hepatitis C, and more than twice influenza’s.
Coronaviruses are also one of the few RNA viruses with a genomic proofreading mechanism — which keeps the virus from accumulating mutations that could weaken it. That ability might be why common antivirals such as ribavirin, which can thwart viruses such as hepatitis C, have failed to subdue SARS-CoV-2. The drugs weaken viruses by inducing mutations. But in the coronaviruses, the proofreader can weed out those changes.
Mutations can have their advantages for viruses. Influenza mutates up to three times more often than coronaviruses do, a pace that enables it to evolve quickly and sidestep vaccines. But coronaviruses have a special trick that gives them a deadly dynamism: they frequently recombine, swapping chunks of their RNA with other coronaviruses. Typically, this is a meaningless trading of like parts between like viruses. But when two distant coronavirus relatives end up in the same cell, recombination can lead to formidable versions that infect new cell types and jump to other species, says Rambaut.
Recombination happens often in bats, which carry 61 viruses known to infect humans; some species harbor as many as 12. In most cases, the viruses don’t harm the bats, and there are several theories about why bats’ immune systems can cope with these invaders. A paper published in February argues that bat cells infected by viruses rapidly release a signal that makes them able to host the virus without killing it.
Estimates for the birth of the first coronavirus vary widely, from 10,000 years ago to 300 million years ago. Scientists are now aware of dozens of strains, seven of which infect humans. Among the four that cause common colds, two (OC43 and HKU1) came from rodents, and the other two (229E and NL63) from bats. The three that cause severe disease — SARS-CoV (the cause of SARS), Middle East respiratory syndrome MERS-CoV and SARS-CoV-2 — all came from bats. But scientists think there is usually an intermediary — an animal infected by the bats that carries the virus into humans. With SARS, the intermediary is thought to be civet cats, which are sold in live-animal markets in China.
The origin of SARS-CoV-2 is still an open question (see ‘Family of killers’). The virus shares 96% of its genetic material with a virus found in a bat in a cave in Yunnan, China — a convincing argument that it came from bats, say researchers. But there’s a crucial difference. The spike proteins of coronaviruses have a unit called a receptor-binding domain, which is central to their success in entering human cells. The SARS-CoV-2 binding domain is particularly efficient, and it differs in important ways from that of the Yunnan bat virus, which seems not to infect people.
Complicating matters, a scaly anteater called the pangolin showed up with a coronavirus that had a receptor-binding domain almost identical to the human version. But the rest of the coronavirus was only 90% genetically similar, so some researchers suspect the pangolin was not the intermediary. The fact that both mutations and recombinations are at work complicates efforts to draw a family tree.
But studies released over the past few months, which have yet to be peer-reviewed, suggest that SARS-CoV-2 — or a very similar ancestor — has been hiding in some animal for decades. According to a paper posted online in March, the coronavirus lineage leading to SARS-CoV-2 split more than 140 years ago from the closely related one seen today in pangolins. Then, sometime in the past 40–70 years, the ancestors of SARS-CoV-2 separated from the bat version, which subsequently lost the effective receptor binding domain that was present in its ancestors (and remains in SARS-CoV-2). A study published on 21 April came up with very similar findings using a different dating method.
These results suggest a long family history, with many coronavirus branches in bats and possibly pangolins carrying the same deadly receptor binding domain as SARS-CoV-2, including some that might have similar abilities to cause a pandemic, says Rasmus Nielsen, an evolutionary biologist at the University of California, Berkeley, and co-author of the second study. “There is a need for continued surveillance and increased vigilance towards the emergence of new viral strains by zoonotic transfer,” he says.
Two open doors
Although the known human coronaviruses can infect many cell types, they all mainly cause respiratory infections. The difference is that the four that cause common colds easily attack the upper respiratory tract, whereas MERS-CoV and SARS-CoV have more difficulty gaining a hold there, but are more successful at infecting cells in the lungs.
SARS-CoV-2, unfortunately, can do both very efficiently. That gives it two places to get a foothold, says Shu-Yuan Xiao, a pathologist at the University of Chicago, Illinois. A neighbor’s cough that sends ten viral particles your way might be enough to start an infection in your throat, but the hair-like cilia found there are likely to do their job and clear the invaders. If the neighbor is closer and coughs 100 particles towards you, the virus might be able get all the way down to the lungs, says Xiao.
These varying capacities might explain why people with COVID-19 have such different experiences. The virus can start in the throat or nose, producing a cough and disrupting taste and smell, and then end there. Or it might work its way down to the lungs and debilitate that organ. How it gets down there, whether it moves cell by cell or somehow gets washed down, is not known, says Stanley Perlman, an immunologist at the University of Iowa in Iowa City who studies coronaviruses.
Clemens-Martin Wendtner, an infectious-disease physician at the Munich Clinic Schwabing in Germany, says it could be a problem with the immune system that lets the virus sneak down into the lungs. Most infected people create neutralizing antibodies that are tailored by the immune system to bind with the virus and block it from entering a cell. But some people seem unable to make them, says Wendtner. That might be why some recover after a week of mild symptoms, whereas others get hit with late-onset lung disease. But the virus can also bypass the throat cells and go straight down into the lungs. Then patients might get pneumonia without the usual mild symptoms such as a cough or low-grade fever that would otherwise come first, says Wendtner. Having these two infection points means that SARS-CoV-2 can mix the transmissibility of the common cold coronaviruses with the lethality of MERS-CoV and SARS-CoV. “It is an unfortunate and dangerous combination of this coronavirus strain,” he says.
The virus’s ability to infect and actively reproduce in the upper respiratory tract was something of a surprise, given that its close genetic relative, SARS-CoV, lacks that ability. Last month, Wendtner published results of experiments in which his team was able to culture virus from the throats of nine people with COVID-19, showing that the virus is actively reproducing and infectious there. That explains a crucial difference between the close relatives. SARS-CoV-2 can shed viral particles from the throat into saliva even before symptoms start, and these can then pass easily from person to person. SARS-CoV was much less effective at making that jump, passing only when symptoms were full-blown, making it easier to contain.
These differences have led to some confusion about the lethality of SARS-CoV-2. Some experts and media reports describe it as less deadly than SARS-CoV because it kills about 1% of the people it infects, whereas SARS-CoV killed at roughly ten times that rate. But Perlman says that’s the wrong way to look at it. SARS-CoV-2 is much better at infecting people, but many of the infections don’t progress to the lungs. “Once it gets down in the lungs, it’s probably just as deadly,” he says.
What it does when it gets down to the lungs is similar in some respects to what respiratory viruses do, although much remains unknown. Like SARS-CoV and influenza, it infects and destroys the alveoli, the tiny sacs in the lungs that shuttle oxygen into the bloodstream. As the cellular barrier dividing these sacs from blood vessels break down, liquid from the vessels leaks in, blocking oxygen from getting to the blood. Other cells, including white blood cells, plug up the airway further. A robust immune response will clear all this out in some patients, but overreaction of the immune system can make the tissue damage worse. If the inflammation and tissue damage are too severe, the lungs never recover and the person dies or is left with scarred lungs, says Xiao. “From a pathological point of view, we don’t see a lot of uniqueness here.”
And as with SARS-CoV, MERS-CoV and animal coronaviruses, the damage doesn’t stop with the lungs. A SARS-CoV-2 infection can trigger an excessive immune response known as a cytokine storm, which can lead to multiple organ failure and death. The virus can also infect the intestines, the heart, the blood, sperm (as can MERS-CoV), the eye and possibly the brain. Damage to the kidney, liver and spleen observed in people with COVID-19 suggests that the virus can be carried in the blood and infect various organs or tissues, says Guan Wei-jie, a pulmonologist at the Guangzhou Institute of Respiratory Health at Guangzhou Medical University, China, an institution lauded for its role in combating SARS and COVID-19. The virus might be able to infect various organs or tissues wherever the blood supply reaches, says Guan.
But although genetic material from the virus is showing up in these various tissues, it is not yet clear whether the damage there is being done by the virus or by a cytokine storm, says Wendtner. “Autopsies are under way in our center. More data will come soon,” he says.
Whether it infects the throat or the lungs, SARS-Cov-2 breaches the protective membrane of host cells using its spike proteins (see ‘Deadly invader’). First, the protein’s receptor-binding domain latches on to a receptor called ACE2, which sits on the surface of the host cell. ACE2 is expressed throughout the body on the lining of the arteries and veins that course through all organs, but it is particularly dense on the cells lining the alveoli and small intestines.
Although the exact mechanisms remain unknown, evidence suggests that after the virus attaches itself, the host cell snips the spike protein at one of its dedicated ‘cleavage sites’, exposing fusion peptides — small chains of amino acids that help to pry open the host cell’s membrane so that the virus’s membrane can merge with it. Once the invader’s genetic material gets inside the cell, the virus commandeers the host’s molecular machinery to produce new viral particles. Then, those progeny exit the cell to go and infect others.
SARS-CoV-2 is uniquely equipped for forcing entry into cells. Both SARS-CoV and SARS-CoV-2 bind with ACE2, but the receptor-binding domain of SARS-CoV-2 is a particularly snug fit. It is 10–20 times more likely to bind ACE2 than is SARS-CoV. Wendtner says that SARS-CoV-2 is so good at infecting the upper respiratory tract that there might even be a second receptor that the virus could use to launch its attack.
Even more troubling is the fact that SARS-COV-2 seems to make use of the enzyme furin from the host to cleave the viral spike protein. This is worrying, researchers say, because furin is abundant in the respiratory tract and found throughout the body. It is used by other formidable viruses, including HIV, influenza, dengue and Ebola to enter cells. By contrast, the cleavage molecules used by SARS-CoV are much less common and not as effective.
Scientists think that the involvement of furin could explain why SARS-CoV-2 is so good at jumping from cell to cell, person to person and possibly animal to human. Robert Garry, a virologist at Tulane University in New Orleans, Louisiana, estimates that it gives SARS-CoV-2 a 100–1,000 times greater chance than SARS-CoV of getting deep into the lungs. “When I saw SARS-CoV-2 had that cleavage site, I did not sleep very well that night,” he says.
The mystery is where the genetic instructions for this particular cleavage site came from. Although the virus probably gained them through recombination, this particular set-up has never been found in any other coronavirus in any species. Pinning down its origin might be the last piece in the puzzle that will determine which animal was the stepping stone that allowed the virus to reach humans.
Some researchers hope that the virus will weaken over time through a series of mutations that adapt it to persist in humans. By this logic, it would become less deadly and have more chances to spread. But researchers have not yet found any sign of such weakening, probably because of the virus’s efficient genetic repair mechanism. “The genome of COVID-19 virus is very stable, and I don’t see any change of pathogenicity that is caused by virus mutation,” says Guo Deyin, who researches coronaviruses at Sun Yat-sen University in Guangzhou.
Rambaut, too, doubts that the virus will become milder over time and spare its host. “It doesn’t work that way,” he says. As long as it can successfully infect new cells, reproduce and transmit to new ones, it doesn’t matter whether it harms the host, he says.
But others think there is a chance for a better outcome. It might give people antibodies that will offer at least partial protection, says Klaus Stöhr, who headed the World Health Organization’s SARS research and epidemiology division. Stöhr says that immunity will not be perfect — people who are reinfected will still develop minor symptoms, the way they do now from the common cold, and there will be rare examples of severe disease. But the virus’s proofreading mechanism means it will not mutate quickly, and people who were infected will retain robust protection, he says.
“By far the most likely scenario is that the virus will continue to spread and infect most of the world population in a relatively short period of time,” says Stöhr, meaning one to two years. “Afterwards, the virus will continue to spread in the human population, likely forever.” Like the four generally mild human coronaviruses, SARS-CoV-2 would then circulate constantly and cause mainly mild upper respiratory tract infections, says Stöhr. For that reason, he adds, vaccines won’t be necessary.
Some previous studies support this argument. One showed that when people were inoculated with the common-cold coronavirus 229E, their antibody levels peaked two weeks later and were only slightly raised after a year. That did not prevent infections a year later, but subsequent infections led to few, if any, symptoms and a shorter period of viral shedding.
The OC43 coronavirus offers a model for where this pandemic might go. That virus also gives humans common colds, but genetic research from the University of Leuven in Belgium suggests that OC43 might have been a killer in the past. That study indicates that OC43 spilled over to humans in around 1890 from cows, which got it from mice. The scientists suggest that OC43 was responsible for a pandemic that killed more than one million people worldwide in 1889–90 — an outbreak previously blamed on influenza. Today, OC43 continues to circulate widely and it might be that continual exposure to the virus keeps the great majority of people immune to it.
But even if that process made OC43 less deadly, it is not yet clear whether something similar would happen with SARS-CoV-2. A study in monkeys showed that they retained antibodies to SARS-CoV-2, but the researchers only reported on the first 28 days after infection, so it is unclear how long the immunity lasted. Concentrations of antibodies against SARS-CoV also dropped significantly over a two- to three-year period. Whether those lowered levels would be enough to prevent infection or reduce severity has not been tested. Cats, cows, dogs and chickens do not seem to become immune to the sometimes deadly coronaviruses that infect them, leaving veterinarians over the years to scramble for vaccines. Despite all the questions about whether people retain any immunity to SARS-CoV-2, some countries are promoting the idea of giving survivors ‘immunity passports’ to allow them to venture out without fear of being infected or infecting others.
Many scientists are reserving judgement on whether the tamer coronaviruses were once as virulent as SARS-CoV-2. People like to think that “the other coronaviruses were terrible and became mild”, says Perlman. “That’s an optimistic way to think about what’s going on now, but we don’t have evidence.”
Mysterious wave of COVID toes still has scientists stumped
Puffy, red-purple, and sometimes painful toes were one of the odder symptoms seen early in the pandemic. But experts are debating their cause—and whether COVID-19 is even to blame.
Lisa Arkin saw more swollen, discolored toes during the early months of the pandemic than she had during her entire career.
Arkin, a pediatric dermatologist at the University of Wisconsin-Madison, treated just a couple of patients with temporary skin lesions called pernio, or chilblains, each year. But in April 2020, when COVID-19 cases first surged, she saw 30 chilblain patients. “My urgent clinics—either telemedicine or in-person—were suddenly filled with patients with purple toes, complaining about swelling, blistering, discomfort, and pain,” Arkin says. “I was completely shocked.”
Dermatologists in other parts of the U.S., and around the world where COVID-19 cases were rising, were also reporting cases of people with red-purple lesions often on their toes. So-called chilblains typically started out with a burning itching sensation on the toes followed by the discoloration, which often resolves without treatment within a few weeks. In some unusual cases, however, the condition lasted for months and even up to a year or more.
“At its most mild, people complain of it being like a mild itch,” says Esther Freeman, a dermatologist and epidemiologist at Harvard Medical School. “At its most severe, it’s so painful that some patients can’t put their shoes on for a couple of weeks.”
Physicians began wondering if the chilblains were due to SARS-CoV-2, the virus that causes COVID-19. In the last two years, scientists have studied thousands of pandemic chilblains or ‘COVID toe’ cases around the world, examining blood and skin biopsies to answer that question. Here’s what we know so far.
What are COVID toes?
It isn’t uncommon for viral infections, including measles, chickenpox, and mononucleosis, to cause a rash of blisters, small bumps, or patches on different parts of the body. These symptoms arise as the body’s immune system responds to the virus or to virus-damaged skin cells.
Similarly, dermatologists have now identified an array of skin conditions, including chilblains, associated with COVID-19. “If you had asked, say, 100 dermatologists before the pandemic what rashes would you expect to see with a virus, pernio chilblains would not have made the list—it would not have made the top 50,” says Freeman. “Chilblains have only rarely been associated with viruses,” she says.
Many of the affected patients—often children and young adults—never developed typical COVID-19 symptoms such as cough, fever, and muscle pain. If they did, their symptoms were mild. The lesions—which typically develop after repeated exposure to cold and damp conditions and can also affect fingers, heels, ears, and nose—usually appeared between one and four weeks after a positive COVID-19 test. However, many COVID toe patients, including several of Arkin’s young patients, had a negative PCR test and lacked antibodies against SARS-CoV-2, suggesting that they probably never had COVID-19.
Similarly, a study conducted in Northern California found that only 17 of 456 patients diagnosed with chilblains between April and December 2020 tested positive for COVID-19 using a PCR test, and only one of 97 who had their blood sampled for SARS-CoV-2-specific antibodies tested positive. This despite a spike in chilblain cases in 2020 compared to those recorded in the region between 2016 and 2019.
“That’s what has made it so hard and confusing to be able to say if it is COVID associated,” Arkin says.
What causes COVID toes?
In some studies, researchers detected the presence of virus particles in the skin biopsies of COVID toe patients, suggesting a SARS-CoV-2 role, but experts aren’t convinced by those findings.
A study published in October last year in the British Journal of Dermatology was among those suggesting an aggressive immune response to a SARS-CoV-2 exposure may be responsible for COVID toes. The researchers studied the blood and skin samples of 50 patients—several of whom had COVID-19 symptoms like cough, fatigue, and fever—who had such chilblains for the first time in April 2020 and tested negative on a PCR test.
The study showed that compared to healthy individuals, COVID toe patients had high levels of immune proteins called autoantibodies in their blood that erroneously damaged their own healthy tissues. They also carried high levels of proteins called type I interferons that are a first line of defense against viral infections.
“The way I explained it to my patients is COVID toes are almost too much of a good thing,” Freeman says. “Your body did a pretty good job of fighting off the virus, and in fact it had a pretty appropriate immune response in that there was a lot of this interferon around. And a side effect of having all this interferon around is that your toes turn purple.”
This potent interferon production may be helping COVID toe patients clear the SARS-CoV-2 infection before COVID-19-specific antibodies form, which could explain why many such patients are negative on antibody tests. Also, the production of certain type I interferons is higher in children and young adults and declines with age, which might explain why COVID toes are more common in that demographic.
Also, “we know people who have interferonopathy, which are genetic diseases where there is too much interferon production, get pernio [chilblain]-like lesions,” says Lindy Fox, a dermatologist at the University of California, San Francisco.
Last year, some individuals also developed such chilblain-like lesions shortly after getting their mRNA COVID-19 vaccine. “Thankfully, it’s not very common,” Freeman says. “But it does seem possible that some patients are mounting a similar interferon response after vaccination, as people do to the virus itself.”
But increased type I interferon levels alone may not explain pandemic chilblains. For instance, patients with viral hepatitis and cancer are treated with interferons to clear the virus or arrest and destroy the growth of cancer cells, yet the interferons don’t induce chilblain-like skin conditions.
Some experts suggest that there may be COVID toe cases that have nothing to do with the virus but something to do with pandemic behavior. People weren’t wearing shoes and socks as much while staying at home, which could have induced pandemic chilblains in some people, says Akiko Iwasaki, an immunologist at Yale University. Though “this would require more analysis,” she says. Until experts are able to trace back a definitive SARS-CoV-2 footprint in COVID toes patients, that association will continue to be subject to speculation. “There’s lots of open questions,” Arkin says, “and may be more mysteries still than answers.”
Why the WHO took two years to say COVID is airborne
Early in the pandemic, the World Health Organization stated that SARS-CoV-2 was not transmitted through the air. That mistake and the prolonged process of correcting it sowed confusion and raises questions about what will happen in the next pandemic.
As 2021 drew to a close, the highly contagious Omicron variant of the pandemic virus was racing around the globe, forcing governments to take drastic actions once again. The Netherlands ordered most businesses to close on 19 December, Ireland set curfews and many countries imposed travel bans in the hope of taming the tsunami of COVID-19 cases filling hospitals. Amid the wave of desperate news around the year-end holidays, one group of researchers hailed a development that had seemed as though it might never arrive. On 23 December, the World Health Organization (WHO) uttered the one word it had previously seemed incapable of applying to the virus SARS-CoV-2: ‘airborne’.
On its website, a page titled ‘Coronavirus disease (COVID-19): How is it transmitted?’ was quietly edited to state that a person can be infected “when infectious particles that pass through the air are inhaled at short range”, a process otherwise known as “short-range aerosol or short-range airborne transmission”. The website says that transmission can occur through “long-range airborne transmission” in poorly ventilated or crowded indoor settings “because aerosols can remain suspended in the air or travel farther than conversational distance”.
“It was a relief to see them finally use the word ‘airborne’, and to say clearly that airborne transmission and aerosol transmission are synonyms,” says aerosol chemist Jose-Luis Jimenez at the University of Colorado Boulder.
The seemingly uncontroversial statement marked a clear shift for the Switzerland-based WHO, which had tweeted categorically early in the pandemic, “FACT: #COVID19 is NOT airborne,” casting the negative in capital letters as if to remove any doubt. At that time, the agency maintained that the virus spreads mainly through droplets produced when a person coughs, sneezes or speaks, an assumption based on decades-old infection-control teachings about how respiratory viruses generally pass from one person to another. The guidance recommended distancing of more than one meter — within which these droplets were thought to fall to the ground — along with hand washing and surface disinfection to stop transfer of droplets to the eyes, nose and mouth.
It took until 20 October 2020 for the agency to acknowledge that aerosols — tiny specks of fluid — can transmit the virus, but the WHO said this was a concern only in specific settings, such as indoor, crowded and inadequately ventilated spaces. Over the next six months, the agency gradually altered its advice to say that aerosols could carry the virus for more than a meter and remain in the air (see ‘Changing views of how COVID spreads’).
But this latest tweak is the WHO’s clearest statement yet about airborne transmission of SARS-CoV-2. And it places the virus among a select group of ‘airborne’ infections, a label long reserved for just a handful of the world’s most virulent pathogens, including measles, chickenpox and tuberculosis.
The change brings the WHO’s messaging in line with what a chorus of aerosol and public-health experts have been trying to get it to say since the earliest days of the outbreak. Many decry the agency’s slowness in stating — unambiguously — that SARS-CoV-2 is airborne. Interviews conducted by Nature with dozens of specialists on disease transmission suggest that the WHO’s reluctance to accept and communicate evidence for airborne transmission was based on a series of problematic assumptions about how respiratory viruses spread.
For example, even in the middle of the fast-moving epidemic, the WHO dismissed field epidemiology reports as proof of airborne transmission because the evidence was not definitive, something that is difficult to achieve quickly during an outbreak. Other criticisms are that the WHO relies on a narrow band of experts, many of whom haven’t studied airborne transmission, and that it eschews a precautionary approach that could have protected countless people in the early stages of the pandemic.
Critics say that inaction at the agency led to national and local health agencies around the world being similarly sluggish in addressing the airborne threat. Having shifted its position incrementally over the past two years, the WHO also failed to adequately communicate its changing position, they say. As a result, it didn’t emphasize early enough and clearly enough the importance of ventilation and indoor masking, key measures that can prevent airborne spread of the virus. Lidia Morawska, an aerosol scientist at the Queensland University of Technology in Brisbane, Australia, spearheaded several efforts to convince the WHO and other health agencies of the airborne threat. She says that airborne transmission was “so obvious” as far back as February 2020, and that omitting it from official guidelines was disastrous.
But Dale Fisher, an infectious-diseases physician at the National University Hospital in Singapore and chair of the WHO’s Global Outbreak Alert and Response Network steering committee, doesn’t think that confusion over whether the virus is airborne has had a defining impact on how the pandemic has played out. “It’s not the cause of the catastrophe we’ve seen,” he says.
Some other researchers defend the agency’s response, given the rapidly evolving situation. “I really don’t think anybody dropped the ball, including WHO,” says Mitchell Schwaber, an infectious-diseases physician at Israel’s ministry of health and an external adviser to the WHO. “So many assumptions that we had about this virus were proven false. We always, we always were learning new things.”
Resolving this debate about how to assess the transmission of respiratory viruses matters, say researchers, because a more deadly variant of SARS-CoV-2 could emerge at any time, and new respiratory viruses will almost certainly plague humanity at some point. It’s not clear whether the WHO and the world will be ready.
Tension in the air
In the final days of March 2020, Morawska contacted dozens of colleagues — an international mix of aerosol scientists, infectious-disease specialists, and building and ventilation engineers — to get the word out about the airborne threat of SARS-CoV-2. On 1 April 2020, the group sent an e-mail laying out their case to Michael Ryan, head of the WHO’s Health Emergencies Program, and Maria Van Kerkhove, technical lead of the WHO’s COVID-19 response.
Within an hour, the agency was on the phone. Two days later, the group attended a video conference with members of the Health Emergencies Program and the Infection Prevention and Control Guidance Development Group (IPC GDG) — an external group of about 40 clinicians and researchers that advises the WHO on infection containment, especially in hospitals. At the time of the meeting, more than one million people had been infected with SARS-CoV-2, and 54,000 had died. Community spread was rampant in several countries.
Morawska presented what she says was a compelling case for airborne transmission. Two facts stood out. First, there was solid evidence that people were becoming infected even when they were more than one meter — the safe distance recommended by the WHO — from a contagious individual. Second, years of mechanistic studies had demonstrated how mucus in a person’s airway can spray into aerosols during speech and accumulate in stagnant rooms. Morawska felt rebuffed by the WHO and its advisers. “I didn’t have a feeling that they were trying to see this from our perspective,” she says.
She and other people who study aerosols and airborne disease transmission say that the IPC GDG is ill-equipped to assess this type of transmission because most of its members have focused on controlling infections in hospitals and they lack expertise in the physics of how airborne contagions spread. At the time of the 1 April meeting, no one in the IPC GDG had studied this type of disease transmission, say critics.
“If it is a new disease, you better include everyone,” says Yuguo Li, a building environment engineer at the University of Hong Kong, whose study of the SARS outbreak in 2002–03 had concluded that the virus responsible, SARS-CoV, probably spread through the airborne route. He suspected that SARS-CoV-2 was also airborne, although he initially thought that only short-range airborne transmission was likely.
Marcel Loomans, an indoor-air-quality physicist at Eindhoven University of Technology in the Netherlands, says that it is often hard to find common ground between the two disciplines. “On the medical side, they were not aware of how aerosols behave in the air and what ventilation can do,” he says. People end up “talking past each other”.
The disconnect was there even in the use of scientific terms. Infection-control experts have long drawn a hard line between droplet viruses and airborne ones, seeing only the latter as capable of travelling far and lingering in the air. “Dogmatic bias is certainly a big part of it,” says Don Milton, an occupational-health physician who studies aerosol transmission of infectious diseases at the University of Maryland in College Park. He says that he was disappointed but not surprised by the WHO’s lack of action in addressing the airborne threat after the 1 April meeting. “I’m just familiar with how the medical profession thinks,” he says.
But Schwaber, who chairs the IPC GDG, recalls the meeting differently. “We took very seriously the issues that they raised at the meeting, and responded to them,” he says. “Nothing was being blown off, nothing was being ignored.”
At the time, he says, the available evidence suggested that airborne precautions throughout hospitals — including N95 masks for staff, visitors and patients — were unnecessary. Still, faced with soaring deaths among frontline doctors and nurses, most hospitals and health agencies adopted these precautions on their COVID-19 wards, as well as less-stringent protections such as wearing surgical masks in other areas of the hospital.
Mark Sobsey, an environmental microbiologist at the University of North Carolina in Chapel Hill who is a member of the IPC GDG, says that especially in the early days, the concerns brought to the WHO about airborne transmission were “largely unfounded” and lacked credible evidence, such as the isolation of infectious virus particles from air samples. Epidemiological data from outbreak investigations were “especially weak”, he says.
According to Trish Greenhalgh, a primary-care health researcher at the University of Oxford, UK, the IPC GDG members were guided by their medical training and the dominant thinking in the medical field about how infectious respiratory diseases spread; this turned out to be flawed in the case of SARS-CoV-2 and could be inaccurate for other viruses as well. These biases led the group to discount relevant information — from laboratory-based aerosol studies and outbreak reports, for instance. So the IPC GDG concluded that airborne transmission was rare or unlikely outside a small set of aerosol-generating medical procedures, such as inserting a breathing tube into a patient.
That viewpoint is clear in a commentary by members of the IPC GDG, including Schwaber, Sobsey and Fisher, published in August 2020. The authors dismissed research using air-flow modelling, case reports describing possible airborne transmission and summaries of evidence for airborne transmission, labelling such reports “opinion pieces”. Instead, they concluded that “SARS-CoV-2 is not spread by the airborne route to any significant extent”.
In effect, the group failed to look at the whole picture that was emerging, says Greenhalgh. “You’ve got to explain all the data, not just the data that you’ve picked to support your view,” and the airborne hypothesis is the best fit for all the data available, she says. One example she cites is the propensity for the virus to transmit in ‘superspreader events’, in which numerous individuals are infected at a single gathering, often by a single person. “Nothing explains some of these superspreader events except aerosol spread,” says Greenhalgh.
Throughout 2020, there was also mounting evidence that indoor spaces posed a much greater risk of infection than outdoor environments did. An analysis of reported outbreaks recorded up to the middle of August 2020 revealed that people were more than 18 times as likely to be infected indoors as outdoors. If heavy droplets or dirty hands had been the main vehicles for transmitting the virus, such a strong discrepancy would not have been observed.
Although the WHO played down the risk of airborne transmission, it did invite Li to become a member of the IPC GDG after he spoke to the group in mid-2020. Had the organization not at least been open to his view that infections were caused by aerosols, especially at short range, “they would not have invited me there as they knew my standing”, he says.
Still, Li is disappointed that it took the WHO until October 2020 to acknowledge that aerosols play a part in disease transmission in community settings. And in its updated guidelines on mask use, in December 2020, the agency still emphasized shortfalls and gaps in the evidence for aerosol transmission, and the need for more “high quality research” to understand the specifics of how the virus spreads. It wasn’t until the end of April 2021 that long-range aerosol transmission was added to a question-and-answer section on the agency’s website about how the virus spreads. And the term airborne wasn’t officially added until December 2021.
Some scientists note that the WHO’s decision to classify SARS-CoV-2 as airborne, belated as it was, is momentous. That’s because it flies in the face of the established view of respiratory virus transmission that held sway when the pandemic began — that nearly all infectious diseases are spread by droplets, not through the air. And researchers say that this change is particularly important because the organization generally takes a conservative approach. “What the WHO says is normally based on a consensus of expert advice and opinion,” says Christopher Dye, an epidemiologist who served as the scientific adviser to the agency’s director-general until 2018.
And although the WHO has drawn strong criticism for the way in which it assessed SARS-CoV-2 transmission, some researchers don’t find the agency’s response surprising. The international community looks to the WHO for early warnings of disease outbreaks. But when it comes to science, the agency “sees its role as certifying the current expert consensus, not (usually) advancing new, tentative knowledge”, says Peter Sandman, an independent risk-communications specialist based in New Jersey who has worked as a consultant to the WHO.
Schwaber says: “Individuals and governments and public-health bodies are looking to a WHO GDG, not to conjecture. They’re looking to a WHO GDG to put out guidance. That everything that we say can be backed by evidence.”
The WHO frequently gets attacked, “so you can understand how they’d be risk averse”, says Tom Frieden, president of the global-health initiative Resolve to Save Lives and former head of the US Centers for Disease Control and Prevention (CDC). Frieden is critical of some aspects of the WHO’s pandemic response, including how slow it was to recommend the use of masks. But he says that the agency is in a difficult position during health crises.
In 2009, for instance, it was accused of being alarmist over the H1N1 swine influenza outbreak that petered out with few lives lost. “WHO got hit hard for that,” says Dye, even though he thinks the agency was right to be cautious and declare a public-health emergency of international concern.
Hard line to tread
Virologist May Chu, a member of the IPC GDG at the Colorado School of Public Health in Aurora, says that the WHO treads a difficult line, and tends to be quite conservative in its recommendations to avoid putting out information that later proves to be incorrect. “You can’t be backtracking” on advice, adds Fisher, because “then you lose complete credibility”.
The gravity of the situation might have made the WHO even more cautious in its pronouncements and less likely to stray from consensus views, according to Sandman’s partner Jody Lanard, an independent risk-communications specialist who has also worked with the WHO in the past.
In previous situations — such as during the Ebola outbreak in West Africa, and in polio vaccine campaigns — the WHO was more nimble than it has been during the COVID-19 pandemic, Lanard says. “I’ve seen them be able to change what their approach was, or try different things,” she says. But during the pandemic “it’s so tempting to be very, very cautious”, because millions of lives will be affected by the agency’s recommendations. Loomans and others question why, when concerns were growing that SARS-CoV-2 could be airborne, the WHO didn’t adopt a precautionary approach by acknowledging the possibility of different risks, even without definitive proof.
And in May 2021, the Independent Panel for Pandemic Preparedness and Response (IPPPR), a body established by the WHO a year earlier to review the agency’s actions at the start of the pandemic, called out the WHO for not applying the precautionary principle to another crucial aspect of COVID-19 transmission — whether it could spread from human to human (see go.nature.com/3iqhfjm). “There is a case for applying the precautionary principle in any outbreak caused by a new pathogen resulting in respiratory infections, and thereby for assuming that human-to-human transmission will occur unless the evidence specifically indicates otherwise,” the IPPPR said in its 2021 report.
In practice, applying the precautionary approach to the question of how SARS-CoV-2 — or any newly emerged pathogen — is transmitted would mean initially assuming that all routes of transmission are possible. “That should be your starting point, and then you can strike out routes if you’re sure,” says Loomans.
But Schwaber says that this approach carries risks. “To say, well, the best interests of the patient and the best interests of the health-care worker involve invoking the precautionary principle would also imply that there’s no downside to invoking it,” he says. Taking full precautions against airborne transmission would require major changes at hospitals, such as using negative-air-pressure isolation rooms and uncomfortable N95 masks for all staff and visitors. Such changes need to be weighed against the evidence that they are required, he says.
Sobsey says that the WHO did adopt the precautionary principle, in part because of the advice from aerosol scientists. That’s why, he says, the agency stated in July 2020 that airborne transmission couldn’t be ruled out — and why it started placing more emphasis on ventilation as a protective measure, even though the evidence for airborne transmission was weak at the time.
“They are not totally wrong,” says Li of those who claimed there were gaps in the evidence for airborne transmission, especially over larger distances. “It’s nothing bad to seek solid scientific evidence,” he says, but “when you see the spread so significantly, do you still wait for a nice Nature or Science article?” he says.
Still, other health organizations moved faster than the WHO despite the uncertainty. In February 2020, Li was contacted by the Chinese Center for Disease Control and Prevention for advice on air conditioning in public buildings and on public transport. At Li’s suggestion, he says, the center recommended maximizing airflow in buildings from the outside, to help flush out any airborne contagion. At the time, Li didn’t think that ventilation would substantially reduce infection from a virus that he suspected was airborne only over short distances — an assumption that he later disproved. But he recommended improved ventilation because “I always support a precautionary approach,” he says.
One thing that’s still missing, says Jimenez, is a clear communication campaign from the WHO. Its director-general, Tedros Adhanom Ghebreyesus, acknowledged the challenges in his opening remarks at the agency’s global conference on communicating science during health emergencies, on 7 June 2021. “Scientific processes, decision-making in an emergency context and mass communication do not fit together easily,” Tedros said, adding that “high-quality research takes time, but time is something we don’t have in an emergency”.
During the early months of the pandemic, the WHO was fighting battles on other fronts. While it grappled with shortages of protective equipment and ventilators, it was also contending with misinformation about unproven treatments for COVID-19 and US threats to pull its funding from the organization.
But critics say that even two years into the pandemic, the WHO hasn’t clearly communicated the risks from airborne transmission. And, perhaps as a result, governments around the world spent much of the pandemic focusing on hand washing and surface cleaning, instead of ventilation and indoor masking.
On 15 December 2021, less than two weeks before the latest change in wording on the WHO’s website, Jimenez put out a call on Twitter for evidence of how governments and organizations either “don’t know how to protect their citizens, or use @WHO’s ambiguity to avoid doing so”. He enumerated more than 100 examples in which health advice at the time was at odds with airborne precautions, indicating that the message was not filtering out from the agency.
Jimenez has continued to receive such examples. Now that the agency has changed the wording on its main website, Jimenez can call out these ‘COVID Hall of Shame’ offenders, as he labels them, for providing advice that is no longer in line with the international health agency.
“That is the arrogance, a bit, of what WHO is,” says Chu. “Once you post [new guidance], it’s pretty passive. They expect you to come to their website. They don’t necessarily broadcast it.”
But that’s exactly what’s needed, says Jimenez, especially given early communications that still haunt the agency, such as its tweet about COVID-19 not being airborne. “No doubt we owe the persistence of misinformation to that WHO announcement and firm position, at the time in which we were all scared and eager to learn how to protect ourselves, very early in the pandemic,” says Jimenez.
The agency defends its actions throughout the pandemic. In a statement to Nature last month, a spokesperson said: “WHO has sought the expertise of engineers, architects and aerobiologists along with expertise in infectious diseases, infection prevention and control, virology, pneumology and other fields since the early days of the COVID-19 pandemic. In August 2020, we established the Environment and Engineering Control Expert Advisory Panel (ECAP) for COVID-19 to provide expert contributions for the development of guidance through evaluation and critical interpretation of available evidence (benefits and harm of interventions) related to relevant technical questions including indoor air quality management and ventilation as an engineering control measure in the context of COVID-19.”
The organization says that initial guidance covered airborne precautions in health-care settings, but notes that: “As the evidence on the transmission of COVID-19 has expanded, we have learnt that smaller-sized infectious particles known as aerosols also play a role in transmission in community settings, and WHO has adapted its guidance and messages to reflect this in the December 2020 update to our mask guidance.”
In response to critics who say that it hasn’t adequately highlighted the changes it has made regarding the risks of airborne transmission, the WHO says that it has held about 250 press briefings and hundreds of live social-media events during the pandemic. It adds that it also pushes out information through social-media channels, meetings with doctors and mailing lists to scientists.
That’s not enough, according to some researchers. Stephanie Dancer, a microbiologist at the Edinburgh Napier University, UK, says that the WHO needs to be clear about its position so that others follow its lead. “They have to show true strength of character and stand up and say, ‘We got it wrong. We’re going to get this right. Here are our next set of guidelines. This is where we’re going to go. This is what we advise,’” she says.
Off to a bad start
Part of the problem was how emphatic the WHO was at the beginning of the pandemic, says Heidi Tworek, a historian and public-policy specialist at the University of British Columbia in Vancouver. “To say that COVID was definitively not airborne unfortunately meant there was a massive hill to climb to undo that,” she says. Right from the beginning, the WHO and other public-health authorities and governments should have emphasized that SARS-CoV-2 was a new coronavirus, and that guidelines would inevitably change, she says. “And when they do, it’s a good thing because it means we know more.”
“We’re really talking here about two failures, not one,” says Sandman. “Being reluctant to change your mind, and being reluctant to tell people you changed your mind.” Like other public-health and scientific organizations, the WHO “are afraid of losing credibility by acknowledging that they got something wrong”, he says.
But when Lanard worked with the WHO in 2005 to draft its risk-communications guidelines, one tenet that she advocated — to admit mistakes and errors when they occur — was removed from the final draft. She says that there were good reasons behind that decision, including that health officials in some countries could have faced imprisonment — or worse — if they had promoted information from the WHO that turned out to be incorrect. Officials and scientific advisers in several countries have received death threats during the pandemic. “Inevitably you’ll get it wrong sometimes,” says Frieden. And the WHO is in a position that means “whatever they do, they get attacked”, he says.
On the science front, questions remain about how much of COVID-19 transmission is airborne. Sobsey says that researchers still need to come up with evidence that the airborne route makes “an important contribution to the overall disease burden”. Many on the other side of the aisle, such as Jimenez, are convinced that airborne transmission predominates. The US Office of Science and Technology Policy voiced strong support for this view on 23 March, when its head, Alondra Nelson, issued a statement called ‘Let’s Clear the Air on COVID’, which said “the most common way COVID-19 is transmitted from one person to another is through tiny airborne particles of the virus hanging in indoor air for minutes or hours after an infected person has been there.”
Other viruses long suspected of being airborne — including influenza and common cold viruses — will also be scrutinized. In September 2021, the US National Institutes of Health awarded Milton a multimillion-dollar grant to conduct trials that will determine whether airborne or droplet routes lead to influenza infection.
Li says that there’s much greater recognition of airborne transmission because of the COVID-19 pandemic, and research over the next few years will probably show that most respiratory viruses can spread in this way. So the whole world will be more alert to the possibility of the airborne threat when old or new infectious diseases start spreading.
In the WHO, too, attitudes have shifted, according to Sobsey. “I think there’s been a sea change in thinking at WHO as a consequence of the experience with this virus,” he says, “which is — be more precautionary, even if you’re not sure.”
Are some people resistant to COVID-19? Geneticists are on the hunt.
Thousands of people repeatedly exposed to the virus never got sick. Scientists hope their DNA may hold clues to new kinds of treatments.
Are some people resistant to COVID-19? Geneticists are on the hunt.
Thousands of people repeatedly exposed to the virus never got sick. Scientists hope their DNA may hold clues to new kinds of treatments.
After dodging COVID-19 several times during the pandemic, flight attendant Angeliki Kaoukaki wondered if she was a medical anomaly. But she’s possibly among a small group of people who might have genetic resistance to the virus. Scientists are now racing to understand how such resistance to COVID-19 could work—and whether the trait can be harnessed to develop new drugs against the disease.
Kaoukaki had already worked alongside other cabin crew members who tested positive without getting sick herself. Then in July 2021 Kaoukaki’s partner contracted a severe case of COVID-19 with high fever and unbearable pain that lasted nearly 10 days. Kaoukaki showed no symptoms, despite the fact that the pair isolated together for two weeks in their studio apartment in Athens, Greece.
She continued to test negative on multiple PCR and rapid antigen tests, and a test she took 23 days after her partner’s confirmed infection revealed no antibodies in her blood.
“Every day I heard [from doctors] that maybe you have COVID,” she says, “but again and again, I tested negative.”
Despite both being vaccinated, her partner got COVID-19 again during the Omicron wave in January. Kaoukaki isolated with him for five days and again showed no symptoms and continued to test negative for the virus. That’s when she began hunting for an explanation.
An online articleled her toEvangelos Andreakos, an immunologist at the Biomedical Research Foundation of the Academy of Athens. He is part of an international consortium called the COVID Human Genetic Effort that has been looking for genetic variations that might reveal why some people never get COVID-19.
Although Andreakos and his colleagues didn’t expect to find many such individuals for their study, they were overwhelmed with emails from at least 5,000 volunteers worldwide with stories similar to Kaoukaki’s. Using saliva samples from the 20 percent of people who met their study criteria, Andreakos and his team will be scanning the protein-coding regions of genes in their DNA to spot any mutations that are absent in the genetic sequences from patients who had severe or moderate cases of COVID-19. The hope is that some of these people harbor the secret to COVID-19 resistance.
“We expect it to be a rare population,” Andreakos says. “But there are precedents.”
Resistance to other viral infections
For a long time, the outcome of any infection was assumed to depend on the genetic traits of the pathogen.
“There used to be a tendency to more think about the pathogen in terms of severity—it’s a severe pathogen or a mild pathogen,” says molecular virologist Johan Nordgren at Sweden’s Linköping University. Relatively less attention was paid to a host and whether their genes affect their ability to fight off an infection, he says.
In the last two decades or so, though, scientists have been conducting so-called genome-wide association studies to identify certain genes or regions of DNA that may be linked to specific diseases. They do this by comparing the genetic sequences of infected individuals with those who are healthy and seeking correlations between mutations and resistance.
Most people have a protein receptor present primarily on the surface of certain immune cells called the chemokine receptor 5, or CCR5. This receptor allows HIV to bind with and enter the cell. But O’Brien’s team discovered that some people have a mutation that produces a defective receptor.
To be resistant, an individual needs two copies of this so-called delta-32 mutation—one from each parent. A single copy can still allow the virus to infect cells, although it slows down the patient’s trajectory to developing AIDS.
“Delta 32 was a hell of a good example that convinced people that genetics was important and that it was possible to have a genetic resistance,” O’Brien says.
Scientists have also tracked down a mutation in a different gene that confers resistance to certain norovirus strains that are a major cause of acute gastroenteritis worldwide. This mutation prevents noroviruses from entering the cells lining the human digestive tract.
“In other words, you either make the port the virus uses to get into the cell, or you do not,” says Lisa Lindesmith, a norovirus researcher at the University of North Carolina at Chapel Hill. “If you don’t, it doesn’t matter how much virus we can give you, you do not get infected.”
While genetic resistance to viral infections isn’t widespread, the fact that it happens at all has ignited interest in similar mutations in COVID-exposed individuals.
Genetic underpinnings to COVID-19 resistance
The COVID Human Genetic Effort started recruiting volunteers last year, with a focus on healthcare workers who were exposed to the virus but didn’t get infected, and healthy adults living in a household with a spouse or partner who got sick and experienced moderate or severe COVID-19 symptoms, like Kaoukaki.
The scientists hypothesized that if these individuals were repeatedly exposed and still escaped infection, they were more likely to carry a mutation that confers resistance to the virus.
One promising target is the gene that codes for the human ACE2 receptor and those that regulate its expression on cell surfaces. The SARS-CoV-2 virus that causes COVID-19 must bind to ACE2 to enter cells and infect them. A mutation that alters its structure and expression might block the virus from binding and prevent infection.
So far, ACE2 seems to be our best bet, says Jean-Laurent Casanova, a geneticist at Rockefeller University who is part of the COVID Human Genetic Effort. Genetic variations that allow ACE2 to function normally but disrupt its interaction with the virus—”these would be good candidate genes,” he says.
It’s possible, though, that there are other biological factors aside from the ACE2 receptor that could explain why some people didn’t develop a SARS-CoV-2 infection.
Some people may possess a robust immune system that produces antiviral proteins called type I interferons, which limit the virus from replicating in human cells. They’re the body’s first line of defense and appear even before antibodies form against the virus.
Another hypothesis is that immune cells called memory T cells that may have formed during previously encountered coronaviruses, like those that cause the common cold, help limit SARS-CoV-2 infection in certain patients.
In 2020, prior to the vaccine rollout, one study found greater presence of memory T cells in healthcare workers who were exposed to the virus but who didn’t develop COVID-19.
The memory T-cells may have cleared the virus very quickly for a few people. But it’s no guarantee these people will be protected from future infections. “In fact, we know some have gone on to get infected with more infectious variants and/or perhaps with a higher dose of the virus,” says Mala Maini, a viral immunologist at the University College London and one of the study authors.
If their study does turn up clues to genetic resistance, Casanova hopes that information could be used to develop therapeutics against COVID-19, similar to the CCR5 inhibitors designed to treat HIV infections. But decisions to develop these therapies, Casanova says, will depend on the nature of the mutated genes discovered.
Even mild COVID-19 can cause your brain to shrink
Recent brain imaging shows the disease can cause physical changes equivalent to a decade of aging and trigger problems with attention and memory. Exactly why is still a mystery.
After being bedridden with fever and coughing for three and half days, Elena Katzap thought COVID-19 was behind her. The writer and teacher in Los Angeles had contracted the virus at the end of January 2022, and she felt grateful that she got only a mild case—she didn’t have breathing difficulties and didn’t need to be hospitalized, and she recovered within days.
“I very specifically remember saying, God it feels so good to be healthy again,” says Katzap. “Then all of a sudden, the very next day it smacked me, and I didn’t know what it was, because it started off with nausea and some stomach issues and some weird forgetfulness.”
Katzap has since experienced an acute loss of memory with poor concentration. She draws blanks in the middle of conversations, and words fail her mid-sentence. “It isn’t physically painful, but it’s so frustrating,” she laments.
Of the roughly 80 million Americans who’ve gotten COVID-19 so far, about one of every four survivors suffers from impaired cognition, commonly described as brain fog. While this isn’t a formal medical term, says Edward Shorter, a professor of psychiatry at University of Toronto, it has become an umbrella term for describing an array of symptoms such as confusion, word-finding difficulties, short-term memory loss, dizziness, or inability to concentrate.
Patients hospitalized with COVID-19 are almost three times more likely than those not hospitalized to have impaired cognition. But brain scans now show that even a mild case of COVID-19 can shrink part of the brain, causing physical changes equivalent to a decade of aging.
“There is evidence of neurologic injury [after COVID-19] that is persistent,” says Ayush Batra, a neurologist at Northwestern University Feinberg School of Medicine. “We are seeing biological and biochemical evidence of it, we are seeing radiographic evidence of it, and most importantly, the patients are complaining of their symptoms. It is affecting their quality of life and day-to-day functioning.” Batra together with his colleagues, has shown chemical indicators of injured brain neurons among long COVID patients with neurologic symptoms.
The drastic impact of COVID-19 on brain
Some of the most compelling evidence of neurological damage after mild COVID-19 comes from U.K. researchers who investigated brain changes in people before and after they got the disease.
The 785 participants, between 51 and 81 years old, who had already been scanned before the start of the pandemic, were scanned on average three years apart as part of the U.K. Biobank project. Tests or medical records showed that 401 of these volunteers had become infected with SARS-CoV-2. Most had mild infections; only 15 of the 401 were hospitalized.
The results showed that four and half months after a mild COVID infection, patients had lost, on average, between 0.2 and 2 percent of brain volume and had thinner gray matter than healthy people. By comparison, older adults lose between 0.2 and 0.3 percent of their gray matter each year in the hippocampus, a region linked to memory.
In the region of the brain linked to smell, the COVID-19 patients had 0.7 percent more tissue damage compared to healthy people.
The infected participants’ performance on cognitive tests also declined more rapidly than before illness. They took 8 and 12 percent longer on the two tests that measured attention, visual screening ability, and processing speed. The patients were not significantly slower on memory recall, reaction time, or reasoning tests.
“We could in turn relate this greater mental ability decline to their greater loss of gray matter in a specific part of the brain,” says Gwenaëlle Douaud, a neuroscientist at the University of Oxford who led the U.K. study.
Overall, studies consistently show that COVID-19 patients score significantly lower in tests of attention, memory, and executive function compared to healthy people. Jacques Hugon, a neurologist at University of Paris Lariboisiere Hospital, says it isn’t clear if the brain will mend itself or whether patients will ever recover, even with cognitive rehabilitation.
“We don’t know exactly what’s going on in the brain,” says Hugon. Perhaps the damage COVID-19 causes in the brain will evolve into various neurodegenerative disorders. “We don’t know that for sure at the moment, but it is a risk, and we need to follow [the patients] very carefully for the years to come.”
What causes brain fog and cognitive decline?
Even before COVID-19, viral infections were known to cause long-lasting cognitive impairments; it is well established that viral infections significantly increase the world’s burden of neurological diseases. While there’s no consensus yet on the exact cause of COVID-19’s cognitive impacts, its effects on various organs can be catastrophic, which means there are many ways the disease can be affecting the brain.
Because COVID-19 affects respiration, it can starve the brain of oxygen, as seen in autopsy data from Finland. In rare cases, COVID-19 can also damage the brain by causing encephalitis, a form of brain inflammation. More broadly, COVID-19 can elicit a severe immune response that triggers a storm of proteins called cytokines, which amplify inflammation throughout the body. Long-term inflammation has been shown to promote cognitive decline and neurodegenerative disease and so could be causing neurodegeneration among COVID-19 survivors.
COVID-19 also increases the risk for blood clots for up to six months, which can cause strokes that deprive the brain tissue of oxygen. One study found large stray bone marrow cells—responsible for the production of blood-clotting platelets—lodged in the brain capillaries of individuals who died from COVID-19 infection. These cells could cause strokes in COVID-19 patients and trigger some neurologic impairments.
Some scientists even fear that COVID-19 survivors could be at higher risk for Alzheimer’s disease, based on evidence for a protein called beta-amyloid in the brains of younger patients who died of COVID-19.
Studies are also accumulating that show direct evidence of the SARS-CoV-2 virus invading the brain. A study by the U.S. National Institutes of Health, currently under review, illustrates how SARS-CoV-2 can spread well beyond the lungs and the respiratory tract. This study suggests that the inability of the immune system to clear the virus from the body could be a potential contributor to long COVID symptoms, including brain fog.
Counting mild COVID-19 cases
Beyond pinpointing the causes, one major concern is that it’s difficult to get an accurate count of how many COVID-19 patients have developed cognitive issues, in part because these symptoms don’t always manifest immediately after infection.
This was the case for Richard Newman, a U.S. Army veteran who is now an IT manager in Houston, Texas. He suffered a severe COVID-19 infection in June 2021 and spent two weeks in the ICU. But he didn’t experience cognitive problems, including trouble recognizing people, until a month after he was discharged from the hospital.
“I knew the face, I knew I was supposed to know them, but I couldn’t remember their name,” says Newman. His symptoms have not improved much eight months after he was first diagnosed with COVID-19. “It is very horrible, it is very debilitating, and it really affects your quality of life,” he says.
At least one study shows that two-thirds of COVID-19 survivors seen at 59 hospitals in the U.S. were diagnosed with cognitive issues during a six-month follow-up. However, as the recent U.K.-based study shows, even mild cases can put people at risk, and tracking those patients will be a challenge if they don’t make the connection between mild COVID-19 and any neurological symptoms that pop up later. Other survivors may be reluctant to mention their experience with COVID-19 and subsequent neurological problems for fear of stigma and discrimination.
Experts also worry that between the wide availability of vaccines and the rise of the relatively milder Omicron variants, people are letting their guard down too soon because they’re not concerned about the possible cognitive damage from getting sick. Although COVID-19 vaccines are highly effective in protecting against serious illness, they do not protect against “long COVID” in people who become infected despite vaccination.
“We need to move away from quantifying the impact of the disease only in terms of deaths and severe cases,” says the University of Oxford’s Douaud, “as evidence from studies on long COVID, and our study, show that even mild infection can be damaging.”
Has The CDC Been Truthful About The Mental Health Impact Of Lockdowns?
At this point, the United States is more than two years into what we were told would be “two weeks to slow the spread.” Life has never been the same since those fateful days in March 2020, when workplaces, schools, and every facet of public life shut their doors at the demand of the government in the name of keeping us safe.
For a few days, it was kind of fun — we got to sleep in a bit and had an excuse to stay at home and watch Netflix. Everyone who wanted an excuse to skip going to the gym now had the best reason ever: they were literally forbidden from doing so. However, forced solitude quickly became old, and people started to get antsy. After all, it’s not natural to be locked up in a cage, with the majority of human interaction coming through Zoom calls.
But beyond slowing down our economy and pace of life, the lockdowns did something else. They wreaked havoc on the public’s mental health.
As the world begins to finally open back up, we’re starting to get a picture of just how dangerous, and in many cases, deadly, lockdowns really were. While we were all affected by government restrictions, there was one group of Americans hurt more than any other: Young people.
While there were definitely early warning signs pointing to the impact of lockdowns on children over the past two years, we now know just how devastating they were. For example, one batch of data released from the Centers for Disease Control and Prevention — the main federal entity that charted America’s approach to lockdowns — revealed that the number of emergency room visits for suspected suicide attempts rose by 51% from February 21-March 21, 2021 among girls age 12-17 compared to the same stretch of time in 2019. This increase came in the aftermath of strict lockdowns and an overall increase in the number of emergency room visits connected to mental health reasons in 2020.
It only got worse from there. Just weeks ago, the CDC unveiled its first national study on the mental health status of high schoolers related to the COVID-19 pandemic, and the results were absolutely devastating.
For starters, 37% of high school students reported poor mental health, and 44% reported a persistent feeling of sadness or hopelessness. One CDC official even admitted that “these data echo a cry for help.”
One major reason for the decline in children’s mental health was that, after being sent home from school, they were often going back to dark environments. Many of their parents had lost their jobs, and countless families were struggling to make ends meet, and as a result, home environments became less stable than usual, and the impact on students was enormous. The study found that 55% of high schoolers reported emotional abuse from their parents, including getting sworn at, insulted, or otherwise put down. A total of 11% even experienced physical abuse, including hitting, beating, or kicking.
Back in April 2020, the National Sexual Assault Hotline revealed a 22% increase in monthly calls from people under 18, with half of all incoming calls coming from minors — a first in the entity’s history. Of those young people who contacted the hotline in March of 2020, 67% identified the perpetrator as a family member, and 79% said they were currently living with that perpetrator. In large part due to forced lockdowns, there was nowhere for these children and adolescents to go in order to get away from their abusers. This story echoed all over the world, from Asia to South America; India’s Childline service, for example, received more than 92,000 calls in 11 days, while in Bolivia, more than four dozen cases of violence against children were reported each day since the lockdowns began.
So what was the true, underlying cause of this mess? According to the CDC, one significant problem was a lack of “school connectedness” — that sense of “being cared for, supported, and belonging at school.” By double-digit margins, children who felt connected to adults and peers at school were less likely to report sadness or hopelessness, to consider suicide, or to actually attempt suicide, but the CDC also noted that only 47% of youth said they felt close to people at school during the COVID-19 pandemic. It is certainly difficult to feel connected at school when the government won’t allow you to actually go to school.
We can also now ask the question of not just what, but who was the true, underlying cause of this mess? As it turns out, the answer is oftentimes the CDC, itself.
In March 2020, the CDC began recommending that schools work with local health officials to determine COVID-19 risk, even suggesting that “extended school dismissals” may be in the cards when high rates of community spread were observed. This was definitely an understandable recommendation to make early on in the pandemic, as the world was still trying to figure out how dangerous COVID-19 actually was.
But within several months after COVID-19 arrived in the United States, however, it was abundantly clear that the disease primarily impacts older adults and those with underlying health issues. Our reporters noted in June of 2020 that the COVID-19 death rate for children in New York City — at that point the American epicenter for the disease — was zero per 100,000, after CDC officials remarked that the actual number of positive COVID-19 cases in the U.S. was probably much higher than the official, reported number of confirmed cases.
Recognizing this reality, a few Western nations kept their schools open without a hitch. Sweden, for example, continued in-person instruction as much as possible, complemented by distance learning technology when teachers had to miss class due to COVID-19 exposure. Throughout the entire pandemic, Sweden reported a mere 23 COVID-19 deaths for children among nearly 500,000 cases. That’s 0.0046%.
Did the CDC adjust their policies based on these observations? No. In fact, more often than not, it seemed that they made decisions based on political expediency, not “the science.”
Emails between the American Federation of Teachers — the nation’s second-largest teachers union — and the CDC showed that the union lobbied to keep schools shuttered and according to The New York Post “even suggested language for the federal agency’s school-reopening guidance” released in February 2021. The AFT spent almost $20 million to elect Democrats in the 2020 election cycle, and their investment definitely paid dividends through their bought-and-paid-for allies in the Biden administration. When confronted by the media, White House Press Secretary Jen Psaki claimed that “it’s actually longstanding best practice for the CDC to engage with organizations, groups that are going to be impacted by guidance and recommendations issued by the agency.”
More recently, a report from the Republicans House Select Subcommittee on the Coronavirus Crisis found that the Biden administration’s CDC had a “cozy relationship” with the AFT on COVID-19 guidelines. In one instance recorded in the report, AFT senior director of health issues Kelly Trautner emailed CDC Director Rochelle Walensky requesting a line be added to upcoming guidance not yet released to the public. Walensky forwarded the line to CDC Center for Preparedness and Response Director Dr. Henry Walke, and it was included in the guidance.
The CDC had the nerve to say that “schools, families, and communities” need to step up and protect children from the fallout of CDC decisions. “What will it take for our schools and communities to help youth withstand the challenges of the COVID-19 pandemic and beyond?” asked one CDC administrator.
It seems that a good place to start is by not trusting the CDC to decide what’s best for children. Maybe that role should’ve stayed with “schools, families, and communities” in the first place.
COVID is spreading in deer. What does that mean for the pandemic?
Hundreds of white-tailed deer in North America have tested positive for SARS-CoV-2. Here’s why scientists aren’t panicking, yet.
Testing deer for SARS-CoV-2 is a little different from testing humans. The cotton swabs travel just a bit farther into the animals’ cavernous nasal passages, for example. “We’ll run out of swab before we, you know, hit anything,” says Andrew Bowman, a veterinary epidemiologist at Ohio State University in Columbus.
And the deer in question are often dead, in the back of a hunter’s truck, at a meat-processing site or a butcher’s shop, waiting to be turned into hamburgers, sausages, steaks, chops and more.
Researchers have worked with hunters for decades as part of regular wildlife surveillance to manage deer populations and track the spread of infectious diseases, such as chronic wasting disease and bovine tuberculosis. But these days, the scientists are also looking for the virus that causes COVID-19 in humans.
In between estimating a deer’s age by checking teeth and taking antler measurements, researchers wearing masks and gloves wipe mud and grass from around the animal’s nostrils before inserting a swab to test for viral RNA. They then collect blood to check for antibodies against the virus. Their work has uncovered widespread infection in white-tailed deer (Odocoileus virginianus) in North America, with hundreds of infected animals in 24 US states and several Canadian provinces.
Scientists want to understand how the virus gets into deer, what happens as it spreads among them, and what risk these infections might pose for other wildlife and for humans. Close to 30 million deer live in the United States — one for every 10 people — and a few million live in Canada.
Several teams have cobbled together the funding to survey deer, says Samira Mubareka, a virologist at Sunnybrook Research Institute in Toronto, Canada.
“We’ve mobilized an army of students,” says Bowman.
The variants researchers found circulating in deer typically mirror those spreading in humans who live nearby, but some studies suggest that SARS-CoV-2 in the wild could already be exploring fresh avenues of evolution through mutations that alter the virus.
It’s not yet clear whether the virus can spread in long chains of infection among deer, or whether deer-to-human transmission could spark outbreaks. But researchers are growing increasingly concerned about the animals becoming a viral reservoir, serving as a recalcitrant source of outbreaks and potentially breeding new variants. Some researchers think that the highly infectious Omicron variant spent time in an animal reservoir before popping up in people.
So far, infected deer aren’t turning up very unwell, but they could spread the infection to livestock or other wildlife that might be more vulnerable. And that’s a major worry. “Once it gets into wildlife,” says Marietjie Venter, a medical virologist at the University of Pretoria in South Africa, “there is basically no way at the moment to control it.”
Researchers have been concerned about wildlife infections since the beginning of the COVID-19 pandemic, but tracking the movements of such a promiscuous virus is tricky. To target surveillance efforts, they started by looking at ACE2, a host-cell protein that the virus typically uses to enter cells. Animals with an ACE2 receptor similar to that found in humans were considered at risk. Teams around the world then began experimentally infecting those animals to see whether they were susceptible and could pass the infection along. Among the prospects were cats, deer mice (Peromyscus maniculatus) and raccoon dogs (Nyctereutes procyonoides), as well as white-tailed deer.
In early January 2021, researchers at the US Department of Agriculture (USDA) showed that fawns in captivity could be infected with SARS-CoV-2, shed it in their nasal mucus and feces, and spread the infection to other fawns in adjacent pens. Within a week, the animals began producing antibodies against the virus, but none was particularly ill.
The results were “somewhat surprising”, because other ungulates, such as cows, sheep and goats, are fairly resistant to infection, says William Karesh, chair of the Paris-based World Organization for Animal Health working group on wildlife.
Thomas DeLiberto, SARS-CoV-2 coordinator in the Wildlife Services program of the USDA Animal and Plant Health Inspection Service in Fort Collins, Colorado, says that the study was an eye-opener. “We said, ‘Well, we better look and see if we’ve had exposure in wild white-tailed deer.’”
DeLiberto and his colleagues started with 385 blood samples collected from deer between January and March 2021, as part of regular wildlife disease-surveillance efforts across Illinois, Michigan, New York and Pennsylvania. Roughly 40% of the samples contained antibodies against SARS-CoV-2. The findings, first reported in a July preprint last year, suggested that the deer had been exposed, but it wasn’t clear whether these were one-off exposures or whether the virus had spread among the animals. It was also possible that the antibodies were the result of other coronavirus infections in deer.
These results led to a slew of fresh deer-sampling efforts across North America, and a rush to publish the results of sampling projects already under way.
In the first year of the pandemic, scientists had begun to collect nasal swabs and blood samples from deer to test for SARS-CoV-2 using the polymerase chain reaction — a positive result would be direct proof that the animals were infected. But until December 2020, “we were getting all negative samples”, says Vanessa Hale, an animal-health researcher at Ohio State University. Everything changed in the new year. She and Bowman found 129 deer that were positive for SARS-CoV-2 viral RNA among about 360 animals sampled in Ohio between January and March 2021.
Suresh Kuchipudi, a virologist at Pennsylvania State University in University Park, and his colleagues got a similar rate of positive tests in Iowa. Of the 283 deer tested between April 2020 and January 2021, 33% were positive for SARS-CoV-2. Most of these turned up in November and December 2020, coinciding with a peak in human infections.
Genome sequencing of more than half of the samples from infected Ohio deer revealed variants similar to those circulating in human communities across the state at the time (see ‘Deer detection’). It seemed that the virus had spilled over from humans on six separate occasions. Mutations in the genetic sequences also confirmed that the deer were spreading the infection among themselves.
Since then, researchers have found positive deer in 24 of the roughly 30 US states where sampling has been reported — as well as in the Canadian provinces of Quebec, Ontario, Saskatchewan, Manitoba, New Brunswick and British Columbia, although the Canadian positivity rates have been lower, at 1–6%.
In late December 2021, researchers found the highly transmissible Omicron variant in white-tailed deer living in Staten Island, a part of New York City. And in March 2022, a mule deer (Odocoileus hemionus) in Utah tested positive for SARS-CoV-2.
The epidemic seems to be confined to North America. “No one’s detected it in European deer so far, despite a lot of looking,” says Rachael Tarlinton, a veterinary virologist at the University of Nottingham, UK. For example, Alex Greenwood, an evolutionary virologist at the Leibniz Institute for Zoo and Wildlife Research in Berlin and his colleagues tested roe deer (Capreolus capreolus), red deer (Cervus elaphus) and fallow deer (Dama dama) in Austria and Germany, and none of them had SARS-CoV-2.
Researchers say biological differences don’t seem to explain the discrepancy. “All the data on ACE2 receptors suggest European deer species should be as susceptible as white-tailed deer,” says Tarlinton. Rather, the North American epidemic seems to be the result of the high density of deer there, and people’s frequent interactions with them.
“In the Americas, the deer basically walk around wild, in people’s backyards,” says Venter, who adds that interactions with large ungulates are much less common where she works. “In Africa, mostly animals would be in wildlife reserves.”
How deer are getting infected remains a mystery. “There’s a window open somewhere and we have no idea what it is,” says Bowman. Humans are known to spread pathogens in the wild, such as the bacterium Escherichia coli, the measles virus and the protozoan Giardia, among others. But these anthroponotic jumps, or ‘spillbacks’, rarely result in sustained transmission, if ever.
Direct contact, for example when people pet or hand-feed animals, could be a culprit. White-tailed deer live in close proximity to people in towns and cities across North America — the deer live near to houses, roam the streets and explore university campuses. “They’ve done very well to adapt to the human-dominated landscape,” says Michael Tonkovich, who oversees the deer program at the Ohio Department of Natural Resources in Athens.
Deer are farmed for meat in some US states, and others have rehabilitation programs for fawns orphaned by car accidents. Deer in captivity can have frequent contact with humans and with wild deer, or they could escape or be released back into the wild.
But Hale says there probably isn’t enough direct contact in any of these scenarios to account for the hundreds of cases detected so far, let alone the countless more that just haven’t been recorded.
Another route of SARS-CoV-2 infection could be environmental. Although transmission through contaminated surfaces has not been an established route in people, deer could be picking the virus up by digging their noses into discarded masks, or gobbling flowers and garden vegetables that humans have sneezed on, for instance. Hunters sometimes also feed and bait deer using maize (corn) or vegetables, which could be covered in virus. But Hale points out that the deer would have to arrive at just the right time to ingest infectious virus. “Is it possible? Yes. Is it likely? Again, I don’t know.”
Another route might be contaminated waste water that trickles into the animals’ water sources. Although many studies have found viral RNA in sewage, they haven’t isolated infectious SARS-CoV-2. Also, it’s not just urban deer that are getting infected; some live in the middle of nowhere, say researchers.
Other animals such as feral cats or wild mink could serve as a go-between for transmission, according to some reports.
“All of these things seem far-fetched until we can prove them,” says Hale. But there doesn’t have to be one single source of infection, says Mubareka. Multiple routes are probably involved.
Once one deer catches the virus, there are plenty of opportunities for SARS-CoV-2 to spread in the broader population. White-tailed deer are very social animals, says Tonkovich. For most of the year, bucks live in loose bachelor groups of up to six, grooming and sparring with each other. Matriarchal does live with several generations of their female offspring and fawns. The animals typically stick to their home ranges of several square kilometers, but this all changes during the breeding season: the winter months from around October to February.
Bucks can travel several tens of kilometers, moving between groups of does and locking antlers with other bucks along the way. Occasionally, a doe might also go on an excursion of up to 100 kilometers, possibly “to visit family or friends”, returning days or weeks later to her usual territory, says Tonkovich. And during heavy snow in some northern states, groups of deer sometimes travel to ‘deer yards’, where thick tree cover prevents snow from accumulating on the ground and where they might encounter other groups. All of this time, the animals are interacting and potentially spreading the virus. There’s a lot of “nose-to-nose contact among deer”, says Linda Saif, a virologist at Ohio State University in Wooster.
All of the potential for viral spread has scientists concerned that deer could become a SARS-CoV-2 reservoir — a permanent home for the virus and a regular source of outbreaks in other animals, including humans. Camels, for example, are a natural reservoir of the MERS-CoV coronavirus that causes Middle East respiratory syndrome, which occasionally jumps to people. Once established in deer, SARS-CoV-2 could mutate, evolve and possibly recombine with other coronaviruses, says Saif. And it could evolve to better infect other grazing animals such as sheep, goats and cows that share pastures with deer, she says. “Once you have a single wild-animal reservoir, it’s conceivable it can pass over to other wildlife, or even domestic livestock.”
There is increasing evidence for that. The virus is showing signs of long-term evolution in deer, for example. In a February preprint, Mubareka and her colleagues sequenced five SARS-CoV-2 genomes from deer sampled in Ontario in November and December 2021. The viruses had 76 mutations compared with the original SARS-CoV-2 virus isolated in Wuhan, China, including some that contribute to amino-acid changes in the spike protein that the virus uses to infect cells. Such mutations have been key to the success of highly transmissible variants.
The closest known relatives the researchers could find for these viral genomes were from people in Michigan almost a year earlier. The results suggested that the virus had been spreading in animals for a long time. “It was crazy. Honestly, I couldn’t believe it,” says Mubareka, adding, “The fact that we found it with such sparse sampling, you really have to wonder what else is going on?”
A second preprint in February9 found the Alpha and Delta SARS-CoV-2 variants in Pennsylvania deer in November 2021. The Alpha genomes were distinct from those found in people, and were found in deer months after Delta had become the dominant human-infecting variant, suggesting that Alpha had been evolving independently in the deer population.
Mubareka and her colleagues made another unexpected finding: a viral sequence in a person from southwestern Ontario that was very similar to the viral genomes found in deer. Although the evidence is not definitive, scientists suspect that the person might have caught the virus from deer.
Deer-to-human transmission, if confirmed, would be concerning, as would reinfection among deer — something Kuchipudi might have observed. From sampling this past December and January, he identified a deer infected with Omicron that also had antibodies against Delta. “If the animals are able to be re-infected, just like people, then the virus will not fade out; it will continue to circulate,” he says.
Researchers say there’s not enough evidence yet to indicate whether deer are a breeding ground for dangerous variants. Karesh says he would need to see many more spillover events — to people from deer — to call them a reservoir for human infection.
Bryan Richards, a wildlife biologist and emerging-disease coordinator at the US Geological Survey National Wildlife Health Center in Madison, Wisconsin, agrees that deer don’t yet seem to pose a risk. “Out of millions of humans who interacted with deer, hunting this last year, we now know of a grand total of one that may have been infected,” he says.
Truly understanding the situation will require more sampling of animals. Some researchers have embarked on longitudinal studies in which they revisit sampling sites over several hunting seasons.
In March 2021, the USDA received a US$300-million grant to survey animals susceptible to SARS-CoV-2, and has sampled deer through the 2022 hunting season in at least 27 states. DeLiberto says his group plans to study footage of how deer interact with people and other animals to quantify their modes of engagement. And Richards says more sampling to determine which types of deer are at highest risk — bucks or does, urban or rural — could offer further clues.
Scientists are also planning more experimental infection studies to see whether variants such as Omicron and Delta behave differently in white-tailed deer, and what other wild animals are susceptible. They’ve found that red foxes (Vulpes vulpes) are, but not coyotes (Canis latrans), and they want to look at mule deer and elk. They might also try mixed-species studies, to see whether, for example, mink can spread the infection to rodents.
A lot more work is needed to track these rapidly unfurling events, says Mubareka. “These are just the early chapters.”
Where did Omicron come from? Three key theories
The highly transmissible variant emerged with a host of unusual mutations. Now scientists are trying to work out how it evolved.
Little more than two months after it was first spotted in South Africa, the Omicron variant of the coronavirus SARS-CoV-2 has spread around the world faster than any previous versions. Scientists have tracked it in more than 120 countries, but remain puzzled by a key question: where did Omicron come from?
There’s no transparent path of transmission linking Omicron to its predecessors. Instead, the variant has an unusual array of mutations, which it evolved entirely outside the view of researchers. Omicron is so different from earlier variants, such as Alpha and Delta, that evolutionary virologists estimate its closest-known genetic ancestor probably dates back to more than a year ago, some time after mid-2020. “It just came out of nowhere,” says Darren Martin, a computational biologist at the University of Cape Town, South Africa.
The question of Omicron’s origins is of more than academic importance. Working out under what conditions this highly transmissible variant arose might help scientists to understand the risk of new variants emerging, and suggest steps to minimize it, says Angela Rasmussen, a virologist at the University of Saskatchewan Vaccine and Infectious Disease Organization in Saskatoon, Canada. “It’s very difficult to try to mitigate a risk that you can’t even remotely wrap your head around,” she says.
The World Health Organization’s recently formed Scientific Advisory Group for the Origins of Novel Pathogens (SAGO) met in January to discuss Omicron’s origins. The group is expected to release a report in early February, according to Marietjie Venter, a medical virologist at the University of Pretoria in South Africa, who chairs SAGO.
Ahead of that report, scientists are investigating three theories. Although researchers have sequenced millions of SARS-CoV-2 genomes, they might simply have missed a series of mutations that eventually led to Omicron. Alternatively, the variant might have evolved mutations in one person, as part of a long-term infection. Or it could have emerged unseen in other animal hosts, such as mice or rats.
For now, whichever idea a researcher favours “often comes down to gut feeling rather than any sort of principled argument”, says Richard Neher, a computational biologist at the University of Basel in Switzerland. “They are all fair game,” says Jinal Bhiman, a medical scientist at the National Institute for Communicable Diseases in Johannesburg, South Africa. “Everyone has their favourite hypothesis.”
Researchers agree that Omicron is a recent arrival. It was first detected in South Africa and Botswana in early November 2021 (see ‘Omicron takeover’); retrospective testing has since found earlier samples from individuals in England on 1 and 3 November, and in South Africa, Nigeria and the United States on 2 November. An analysis of the mutation rate in hundreds of sequenced genomes, and of how quickly the virus had spread through populations by December, dates its emergence to not long before that — around the end of September or early October last year. In southern Africa, Omicron probably spread from the dense urban province of Gauteng, between Johannesburg and Pretoria, to other provinces and to neighbouring Botswana.
But because Johannesburg is home to the largest airport on the African continent, the variant could have emerged anywhere in the world — merely being picked up in South Africa because of the country’s sophisticated genetic surveillance, says Tulio de Oliveira, a bioinformatician at the University of KwaZulu-Natal in Durban and at Stellenbosch University’s Centre for Epidemic Response and Innovation, who has led South Africa’s efforts to track viral variants, including Omicron.
What stands out about Omicron is its remarkable number of mutations. Martin heard about it when he took a phone call from de Oliveira, who asked him to look at the craziest SARS-CoV-2 genome he had ever seen.
The variant has more than 50 mutations when compared with the original SARS-CoV-2 virus isolated in Wuhan, China (see go.nature.com/32utxva). Some 30 of these contribute to changes in amino acids in the spike protein, which the coronavirus uses to attach to and fuse with cells. Previous variants of concern have had no more than ten such spike mutations. “That is a hell of a lot of changes,” says Neher.
Researchers have seen many of these mutations before. Some were previously known to give the virus an increased ability to bind to the ACE2 receptor protein — which adorns host cells and is the docking point for SARS-CoV-2 — or to help it evade the body’s immune system. Omicron forms a stronger grip on ACE2 than do previously seen variants. It is also better at evading the virus-blocking ‘neutralizing’ antibodies produced by people who have been vaccinated, or who have been infected with earlier variants. Other changes in the spike protein seem to have modified how Omicron enters cells: it appears to be less adept at fusing directly with the cell’s membrane, and instead tends to gain entry after being engulfed in an endosome (a lipid-surrounded bubble).
But more than a dozen of Omicron’s mutations are extremely rare: some have not been seen at all before, and others have popped up but disappeared again quickly, presumably because they gave the virus a disadvantage.
Another curious feature of Omicron is that, from a genomic viewpoint, it consists of three distinct sublineages (called BA.1, BA.2 and BA.3) that all seem to have emerged at around the same time — two of which have taken off globally. That means Omicron had time to diversify before scientists noticed it. Any theory about its origins has to take this feature into account, as well as the number of mutations, notes Joel Wertheim, a molecular epidemiologist at the University of California, San Diego.
Researchers have explained the emergence of previous variants of concern through a simple process of gradual evolution. As SARS-CoV-2 replicates and transmits from person to person, random changes crop up in its RNA sequence, some of which persist. Scientists have observed that, in a given lineage, about one or two single-letter mutations a month make it into the general viral circulation — a mutation rate about half that of influenza. It is also possible for chunks of coronavirus genomes to shuffle and recombine wholesale, adds Kristian Andersen, an infectious-disease researcher at Scripps Research in La Jolla, California. And viruses can evolve faster when there is selection pressure, he says, because mutations are more likely to stick around if they give the virus an increased ability to propagate under certain environmental conditions.
Some scientists think that person-to-person spread would not be conducive to accumulating as many changes as Omicron has since mid-2020. “It does seem like a year and a half is a really short period of time for that many mutations to emerge and to apparently be selected for,” says Rasmussen.
But Bhiman argues that enough time has elapsed. She thinks the mutation process could have occurred unseen, in a region of the world that has limited genomic sequencing and among people who don’t typically get tested, perhaps because they didn’t have symptoms. At some point in the past few months, she says, something happened to help Omicron explode, maybe because the progress of other variants — such as Delta — was gradually impeded by the immunity built up from vaccination and previous infection, whereas Omicron was able to evade this barrier.
Although researchers have submitted almost 7.5 million SARS-CoV-2 sequences to the GISAID genome database, hundreds of millions of viral genomes from people with COVID-19 worldwide have not been sequenced. South Africa, with some 28,000 genomes, has sequenced less than 1% of its known COVID-19 cases, and many nearby countries, from Tanzania to Zimbabwe and Mozambique, have submitted fewer than 1,000 sequences to GISAID (see ‘Missing genomes’).
Martin says that researchers need to sequence SARS-CoV-2 genomes from these countries to get a better sense of the likelihood of unobserved evolution. It is possible that the three sublineages of Omicron each separately arrived in South Africa from a region with limited sequencing capacity, he says.
But de Oliveira says the scenario that Omicron evolved unseen through person-to-person transmission is “extremely implausible”. Intermediate steps in Omicron’s evolution should have been picked up in viral genomes from people travelling from countries that do little sequencing to those that do a lot.
“This is not the nineteenth century, where you take six months to go from point to point by sailboat,” says Sergei Pond, a computational evolutionary biologist at Temple University in Philadelphia, Pennsylvania.
And Andersen adds that, because some of Omicron’s mutations haven’t been seen before, the variant might have evolved in an environment not involving person-to-person chains of transmission. Some of the changes in Omicron don’t match any seen even in the broader viral group of sarbecoviruses, which includes the virus that causes severe acute respiratory syndrome (SARS). For example, one particular site on the genomes of all known sarbecoviruses encodes a serine amino acid, but a mutation in Omicron means the variant has a lysine at that position, which changes the biochemistry of that region, Andersen says.
However, says Jesse Bloom, a viral evolutionary geneticist at the Fred Hutchinson Cancer Research Center in Seattle, Washington, SARS-CoV-2 has not yet explored all of its possibilities in people. “The virus is still expanding in the evolutionary space.”
An alternative incubator for fast-paced evolution is a person with a chronic infection. There, the virus can multiply for weeks or months, and different types of mutation can emerge to dodge the body’s immune system. Chronic infections give the virus “the opportunity to play cat and mouse with the immune system”, says Pond, who thinks it is a plausible hypothesis for Omicron’s emergence.
Such chronic infections have been observed in people with compromised immune systems who cannot easily get rid of SARS-CoV-2. For example, a December 2020 case report described a 45-year-old man with a persistent infection. During almost five months in its host, SARS-CoV-2 accumulated close to a dozen amino-acid changes in its spike protein. Some researchers suggest Alpha emerged in someone with a chronic infection, because, like Omicron, it seems to have accumulated changes at an accelerated rate.
“The virus has to change to stick around,” says Ben Murrell, an interdisciplinary virologist at the Karolinska Institute in Stockholm. The receptor-binding domain, where many of Omicron’s mutations are concentrated, is an easy target for antibodies, and probably comes under pressure to change in a long-term infection.
But none of the viruses from individuals with chronic infections studied so far has had the scale of mutations observed in Omicron. Achieving that would require high rates of viral replication for a long time, which would presumably make that person very unwell, says Rasmussen. “It seems like a lot of mutations for just one person.”
Further complicating the picture, Omicron’s properties could stem from combinations of mutations working together. For example, two mutations found in Omicron — N501Y together with Q498R — increase a variant’s ability to bind to the ACE2 protein by almost 20 times, according to cell studies. Preliminary research by Martin and his colleagues suggests that the dozen or so rare mutations in Omicron form three separate clusters, in which they seem to work together to compensate for the negative effects of any single one.
If this is the case, it means that the virus would have to replicate sufficiently in a person’s body to explore the effects of combinations of mutations — which would take longer to achieve than if it were sampling the space of possible mutations one by one.
One possibility is that multiple individuals with chronic infections were involved, or that Omicron’s ancestor came from someone with a long-term infection and then spent some time in the general population before being detected. “There are a lot of open questions,” says Rasmussen.
Proving this theory is close to impossible, because researchers would need to be lucky enough to find the particular person or group that could have sparked Omicron’s emergence. Still, more comprehensive studies of SARS-CoV-2’s evolution in chronic infections would help to map out the range of possibilities, says Neher.
Mouse or rat
Omicron might not have emerged in a person at all. SARS-CoV-2 is a promiscuous virus: it has spread to a wild leopard, to hyenas and hippopotamuses at zoos, and into pet ferrets and hamsters. It has caused havoc in mink farms across Europe, and has infiltrated populations of white-tailed deer throughout North America. And Omicron might be able to enter a broader selection of animals. Cell-based studies have found that, unlike earlier variants, Omicron’s spike protein can bind to the ACE2 protein of turkeys, chickens and mice.
One study found that the N501Y–Q498R combination of mutations allows variants to bind tightly to rat ACE2. And Robert Garry, a virologist at Tulane University in New Orleans, Louisiana, notes that several other mutations in Omicron have been seen in SARS-CoV-2 viruses adapting to rodents in laboratory experiments.
The types of single-nucleotide substitution observed in Omicron’s genome also seem to reflect those typically observed when coronaviruses evolve in mice, and do not match as well with the switches that are observed in coronaviruses adapting to people, according to a study of 45 mutations in Omicron. The study noted that, in human hosts, G to U substitutions tend to occur in RNA viruses at a higher rate than C to A switches do, but that Omicron does not show this pattern.
It is possible, then, that SARS-CoV-2 could have acquired mutations that gave it access to rats — jumping from an ill person to a rat, possibly through contaminated sewage — and then spread and evolved into Omicron in that animal population. An infected rat could later have come into contact with a person, sparking the emergence of Omicron. The three sublineages of Omicron are sufficiently distinct that, according to this theory, each would represent a separate jump from animal to human.
A large population of animals with infections lasting longer than in humans could give SARS-CoV-2 room to explore a wide diversity of mutations and “build up a large ghost population of viruses that no one knows about”, says Martin, who says he finds this ‘reverse zoonosis’ theory convincing. Changes that make the virus better at spreading in its animal host won’t necessarily affect its ability to infect people, he says.
An animal reservoir could also explain why some of the mutations in Omicron have been rarely seen before in people, says Andersen.
In the dark
But others say that even a single viral jump from an animal to a person is a rare event — let alone three. Meanwhile, the virus has had plenty of opportunities to slip between people. And although some of Omicron’s mutations have been seen in rodents, that doesn’t mean they can’t happen or haven’t occurred in people, too, and have simply been missed.
Murrell also points out that SARS-CoV-2 didn’t immediately go through a period of accelerated evolution after jumping to people for the first time. When it spread to mink and deer, it did pick up changes, but not as many mutations as Omicron has accumulated, says Spyros Lytras, an evolutionary virologist at the University of Glasgow, UK. This means that the evidence isn’t sufficient to suggest Omicron’s predecessor would have undergone rapid selection after finding a new home in the wild.
To confirm this theory, researchers would need to find close relatives of Omicron in another animal, but they haven’t been looking — “something that has been horribly neglected”, says Martin. Since the pandemic began, researchers have sequenced fewer than 2,000 SARS-CoV-2 genomes isolated from other animals, mostly from mink, cats and deer.
Now that Omicron has taken off, how it evolves in people could offer more clues about its origins. It might, for instance, shed mutations that, in retrospect, are found to have helped it adapt to a different animal host, or in a person with a chronic infection. But it could also not change by much, leaving researchers in the dark.
The answer to Omicron’s emergence will probably be one or a combination of the three scenarios, says Bloom. But, he adds, researchers are far from explaining the processes that brought Omicron here, let alone predicting what the next variant will look like.
And many scientists say they might never find out where Omicron came from. “Omicron really shows us the need for humility in thinking about our ability to understand the processes that are shaping the evolution of viruses like SARS-CoV-2,” says Bloom.
CDC Tracked Phones To Check If Americans Followed Lockdown Orders
Recently released documents from the Centers for Disease Control show the agency tracked location data on millions of phones to monitor whether Americans were obeying COVID-19 lockdown orders. The CDC spent $420,000 on location data in order to track a number of things, including compliance with curfews and people visiting K-12 schools.
The CDC bought location data, which is sourced from a person’s phone and can show where they travel, including where they live and work. The data the CDC had was aggregated, which meant it would only show broad movements and trends, rather than information specific to individuals, but that data could theoretically be used to track specific individuals. The CDC had information from at least 20 million people who actively use their cell phones.
The documents, which were obtained via a Freedom of Information Act request from Vice’s Motherboard, show the agency used the data to hourly monitor activity in COVID-19 curfew zones. They also checked the number of people visiting participating pharmacies and for vaccine monitoring. The CDC also listed a number of “potential use cases” for the data, which included tracking the patterns of people who visited K-12 schools and comparing those patterns to 2019 numbers. Another potential use case involved examining the correlation between people’s movements and a rise in COVID-19 cases.
It doesn’t appear as if the tracking was limited to COVID-19. The documents indicated that the CDC used research data for “physical activity and chronic disease prevention such as visits to parks, gyms, or weight management businesses.” In addition to tracking physical activity, the CDC said it also planned to use the mobility data for “non-Covid-19 programmatic areas and public health priorities,” including the monitoring of people traveling to greenspaces, modes of travel, and “population migration before, during, and after natural disasters.” The information gathered will be available for everyone at the CDC.
Motherboard spoke with a cybersecurity expert who said, “The CDC seems to have purposefully created an open-ended list of use cases, which included monitoring curfews, neighbor-to-neighbor visits, visits to churches, schools and pharmacies, and also a variety of analysis with this data specifically focused on ‘violence.”
It looks like the CDC plans to continue tracking American phones. The agency said it has an “interest in continued access to this mobility data as the country opens back up.” The CDC also said the data was used by “several teams/groups” during the pandemic response, which resulted in “deeper insights” into the pandemic “as it pertains to human behavior.”
Big Picture: The data bought by the CDC doesn’t show the location of specific devices, but search results can point to specific locations, which could allow someone with nefarious intent to use the data to unmask individual users. Multiple researchers have been able to show this is possible using this type of data.
Covid: World’s true pandemic death toll nearly 15 million, says WHO
The Covid pandemic has caused the deaths of nearly 15 million people around the world, the World Health Organization (WHO) estimates.
That is 13% more deaths than normally expected over two years.
The WHO believes many countries undercounted the numbers who died from Covid – only 5.4 million were reported.
In India, there were 4.7 million Covid deaths, it says – 10 times the official figures – and almost a third of Covid deaths globally.
The Indian government has questioned the estimate, saying it has “concerns” about the methodology, but other studies have come to similar conclusions about the scale of deaths in the country.
The measure used by the WHO is called excess deaths – how many more people died than would normally be expected based on mortality in the same area before the pandemic hit.
These calculations also take into account deaths which were not directly because of Covid but instead caused by its knock-on effects, like people being unable to access hospitals for the care they needed. It also accounts for poor record-keeping in some regions, and sparse testing at the start of the crisis.
But the WHO said the majority of the extra 9.5 million deaths seen above the 5.4 million Covid deaths reported were thought to be direct deaths caused by the virus, rather than indirect deaths.
Speaking about the scale of the figures, Dr Samira Asma, from the WHO’s data department, said “It’s a tragedy.
“It’s a staggering number and it’s important for us to honour the lives that are lost, and we have to hold policymakers accountable,” she said.
“If we don’t count the dead, we will miss the opportunity to be better prepared for the next time.”
Alongside India, countries with the highest total excess deaths included Russia, Indonesia, USA, Brazil, Mexico and Peru, the WHO figures suggest. The numbers for Russia are three-and-a-half times the country’s recorded deaths.
The report also looks at the rates of excess deaths relative to each country’s population size. The UK’s excess mortality rate – like America, Spain and Germany – was above the global average during 2020 and 2021.
Countries with low excess mortality rates included China, which is still pursuing a policy of “zero Covid” involving mass testing and quarantines, Australia, which imposed strict travel restrictions to keep the virus out of the country, Japan and Norway.
The academics who helped compile the report admit their estimates are more speculative for countries in sub-Saharan Africa, because there is little data on deaths in the region. There were no reliable statistics for 41 out of 54 countries in Africa.
Statistician Prof Jon Wakefield, from Seattle’s University of Washington, helped the WHO and told the BBC: “We urgently need better data collection systems.
“It is a disgrace that people can be born and die – and we have no record of their passing.
“So we really need to invest in countries’ registration systems so we can get accurate and timely data.”
Flu vaccine could cut COVID risk
Health-care workers who got the influenza vaccine were also protected from COVID-19 — but the effect might not last long.
Influenza vaccines have a surprising health benefit: they might also prevent COVID-19, particularly in its most severe forms.
A study of more than 30,000 health-care workers in Qatar found that those who got a flu jab were nearly 90% less likely to develop severe COVID-19 over the next few months, compared with those who hadn’t been recently vaccinated against flu.
The study, which was conducted in late 2020, before the roll-out of COVID-19 vaccines, is in line with previous work suggesting that ramping up the immune system using influenza vaccines and other jabs could help the body to fend off the coronavirus SARS-CoV-2.
In the early months of the pandemic — while COVID-19 vaccines were still in development — researchers were intensely interested in the possibility that existing vaccines might provide some protection against SARS-CoV-2. But collecting strong evidence for such an effect is difficult, because people who seek vaccination for diseases other than COVID-19 might also make other choices that reduce their risk of being infected with SARS-CoV-2.
To minimize the impact of this ‘healthy-user effect’, a team led by Laith Jamal Abu-Raddad, an infectious-disease epidemiologist at Weill Cornell Medicine–Qatar in Doha, analyzed the health records of 30,774 medical workers in the country. There is probably less variation in health-related behavior among such workers than in the general population, reducing — but probably not eliminating — bias, Abu-Raddad says.
The researchers tracked 518 workers who tested positive for SARS-CoV-2 and matched them to more than 2,000 study participants who had tested negative for the virus. Those who had received an influenza vaccine that season were 30% less likely to test positive for SARS-CoV-2, and 89% less likely to develop severe COVID-19, compared with workers who had not (although the number of severe cases was small in both groups). The study was posted on the medRxiv preprint server on 10 May.
Günther Fink, an epidemiologist at the University of Basel in Switzerland, says the Qatar analysis reduces the odds that other studies that uncovered the same link were a fluke. His team reported that flu vaccines were associated with a reduced risk of death in people hospitalized with COVID-19 in Brazil.
“This is an important piece of evidence,” says Mihai Netea, an infectious-disease specialist at Radboud University Medical Center in Nijmegen, the Netherlands. The observation that influenza vaccines are linked to a reduction in not just SARS-CoV-2 infections, but also disease severity, strongly suggests that the protection is genuine, he adds.
How long this protection lasts is unclear. Among those in the Qatar study who had the flu jab and later contracted COVID-19, Abu-Raddad’s team recorded SARS-CoV-2 infections occurring, on average, about six weeks after vaccination. “I don’t expect to see this effect lasting long at all,” he says. Netea guesses that the benefits last for between six months and two years.
It’s not fully clear why flu vaccines — which are composed of killed influenza viruses — would also protect against COVID-19. Vaccines train the immune system to recognize specific pathogens, but they also rev up broad-acting antiviral defences, says Netea, who has found signs of such responses in flu-vaccine recipients.
Netea’s team is also working to better quantify the benefits of vaccines targeting influenza and other diseases against COVID-19. To fully rule out healthy-user effects, his team has launched a randomized, placebo-controlled trial in Brazil that will test whether influenza and measles–mumps–rubella vaccines can protect against COVID-19.
Knowing that vaccines for flu and other diseases can offer protection against COVID-19, even if only partial and for a limited period, could limit the damage caused by a future pandemic before a vaccine for that disease is developed, Netea argues. “If you have something in the beginning, you could save millions of lives.”
How long does COVID-19 linger in your body? New report offers clues.
A comprehensive study found that viral remnants can survive for months after infection in certain people, perhaps causing some symptoms of long COVID.
Most COVID-19 patients recover from their acute infection within two weeks, but bits of the virus don’t always disappear from patients’ bodies immediately. Now a new study, one of the largest focusing on hospitalized COVID-19 patients, shows that some patients harbor these viral remnants for weeks to months after their primary COVID-19 symptoms resolve.
The study suggests that when the genetic material of the virus, called RNA, lingers in the body longer than 14 days, patients may face worse disease outcomes, experience delirium, stay longer in the hospital, and have a higher risk of dying from COVID-19 compared with those who cleared the virus rapidly. The persistence of the virus may also play a role in long COVID, the debilitating suite of symptoms that can last for months. Estimates suggest between 7.7 and 23 million people in the United States alone are now affected by long COVID.
Without immunity from vaccination or a previous infection, SARS-CoV-2—the virus that causes COVID-19—replicates and spreads throughout the body and is shed through the nose, mouth, and gut. But for most infected people, virus levels in the body peak between three and six days after the original infection, and the immune system clears the pathogen within 10 days. The virus shed after this period is generally not infectious.
Even after accounting for disease severity, whether the patients were intubated, or had underlying medical comorbidities, “there is something here that signals that patients who are persistently PCR positive have worse outcomes,” says Ayush Batra, a neurologist at Northwestern University Feinberg School of Medicine, who led the new study.
Batra’s study shows that patients who had prolonged shedding during an acute infection risk more severe outcomes from COVID-19, says Timothy Henrich, a virologist and immunologist at the University of California, San Francisco who was not involved in the new research. But the study doesn’t investigate whether this persistent virus is directly responsible for long COVID.
“There are multiple leading hypotheses out there about the cause of long COVID, including viral persistence, and it may be that there are multiple pathways at play, perhaps to some varying degree in any one person,” says Linda Geng, a doctor at Stanford Health Care who co-directs a newly opened Post-Acute COVID-19 Syndrome Clinic for treating long COVID sufferers.
Persisting virus causes worse COVID-19 outcomes
Batra and his team began studying persistent coronavirus infections after observing that some patients who were returning to the hospital were still testing positive for the virus four or five weeks after they were diagnosed with the initial infection.
For their new study, the team analyzed 2,518 COVID-19 patients hospitalized in the Northwestern Medicine Healthcare system between March and August 2020. They focused on PCR tests, which are considered the gold standard, because such tests detect genetic material from the virus and so are highly sensitive and less likely to return false negatives.
The team found that 42 percent of patients continued to test PCR positive two weeks or longer after their initial diagnosis. After more than 90 days, 12 percent of the persistent shedders were still testing positive; one person tested positive 269 days after the original infection.
Viral persistence has been noted before in previous smaller studies. Researchers showed that even patients without obvious COVID-19 symptoms harbored SARS-CoV-2 for a couple of months and beyond. In some immunocompromised patients, the virus may not be cleared for a year. Four percent of COVID-19 patients in a trial on chronic COVID-19 infection at Stanford continued to shed viral RNA in feces seven months after diagnosis. However, Batra’s study illustrates that a larger number of patients take longer to clear the virus than previously realized.
“Persistent RNA shedding would mean that there still is a reservoir of virus somewhere in the body,” says Michael VanElzakker, a neuroscientist affiliated with Massachusetts General Hospital, Harvard Medical School and Tufts University. Such reservoirs are thought to allow the virus to persist over a long period of time and could trigger the immune system to act aberrantly, perhaps causing long COVID.
“Some patients, for variety of reasons, are not able to clear this reservoir, or their immune system reacts in some abnormal way that results in these persistent symptoms that have come to be termed as long COVID,” says Batra.
Still, many scientists don’t think there is sufficient evidence yet to link the persistence of viral RNA to long COVID.
The list of human tissues where SARS-CoV-2 hides long after the initial infection is growing. Studies have identified the virus, or genetic material from it, in the intestines of patients four months after initial infection, and inside the lung of a deceased donor more than a hundred days after recovery from COVID-19. One study that’s not yet peer reviewed also detected the virus in the appendix and breast tissues 175 and 462 days, respectively, after coronavirus infections. And research from the U.S. National Institutes of Health that’s also not yet peer reviewed detected SARS-CoV-2 RNA persisting at low levels across multiple tissues for more than seven months, even when it was undetectable in blood.
“It is not surprising to find viruses encountered during the lifetime” surviving in human tissues, says Kei Sato, a virologist at the University of Tokyo. Indeed, Sato’s work has shown that humans frequently accumulate viruses such as Epstein-Barr virus, varicella zoster virus (which causes chicken pox), and many herpes viruses in dormant forms. These persisting viruses are typically present at low levels, so only extensive genetic sequencing can identify them.
This highlights how complicated it is to prove or disprove the association between persisting SARS-CoV-2 and long COVID. Shingles, for example, occurs decades after a chickenpox infection, when the latent virus gets reactivated during immune stress.
Likewise, lingering SARS-CoV-2 could cause long-term health problems. Henrich thinks when the virus is seeded in deep tissues, it potentially causes the immune system to shift into a dysregulated inflammatory state. Such a state is “probably evidence that the virus is capable of persisting, and maybe getting down into sort of an uneasy truce with the body,” says VanElzakker.
Still, associating any lingering virus with long COVID will require extensive studies. “We still don’t know enough to make strong conclusions about any of the current proposed mechanisms, but research is actively underway to answer those questions,” says Geng.
Clearing up persistent virus might cure long COVID
Both Geng and Henrich’s groups have reported preliminary case studies that show an improvement in long COVID symptoms after patients were treated with Pfizer’s COVID-19 oral antiviral Paxlovid. Paxlovid stops the virus from replicating, which is why some experts think it can clear any lingering virus. But both authors urge caution before assuming that Paxlovid will be safe, effective, or sufficient and thereby a reliable cure for long COVID.
“There are some interesting hypotheses about how Paxlovid may be useful in the treatment of long COVID, but we’d need further investigation and clinical trials before coming to any conclusions,” says Geng.
The U.S. Food and Drug Administration has warned against off-label uses of Paxlovid, which is not approved for long COVID treatment. The agency has given Paxlovid an emergency use authorization to treat mild to moderate COVID-19 in those who are at risk of developing severe disease, twice daily for five days soon after a positive test.
“It would be important to consider the optimal duration of treatment [of Paxlovid] to ensure long-term and sustained results,” says Geng.
President Joe Biden has directed the secretary of Health and Human Services to create a national action plan on long COVID, and the NIH has launched a multi-year study called RECOVER to understand, prevent, and treat long-term health effects related to COVID-19.
In the meantime, vaccines not only continue to protect against severe disease, but evidence is also emerging that they can prevent many long COVID symptoms. One new study compared 1.5 million unvaccinated COVID-19 patients to 25,225 vaccinated patients with breakthrough infections, and it found that vaccines significantly reduced the risk of developing long COVID symptoms 28 days after an infection. The protective effect of vaccination got even larger at 90 days post-infection.
“Although a majority of people do not develop long COVID, it’s certainly a risk, and COVID doesn’t stop after the first 10 days of becoming infected,” says Henrich. “For those who don’t take COVID seriously, it can be life changing.”
Viruses that were on hiatus during Covid are back — and behaving in unexpected ways
For nearly two years, as the Covid pandemic disrupted life around the globe, other infectious diseases were in retreat. Now, as the world rapidly dismantles the measures put in place to slow spread of Covid, the viral and bacterial nuisances that were on hiatus are returning — and behaving in unexpected ways.
Consider what we’ve been seeing of late.
The past two winters were among the mildest influenza seasons on record, but flu hospitalizations have picked up in the last few weeks — in May! Adenovirus type 41, previously thought to cause fairly innocuous bouts of gastrointestinal illness, may be triggering severe hepatitis in healthy young children.
Respiratory syncytial virus, or RSV, a bug that normally causes disease in the winter, touched off large outbreaks of illness in kids last summer and in the early fall in the United States and Europe.
And now monkeypox, a virus generally only found in West and Central Africa, is causing an unprecedented outbreak in more than a dozen countries in Europe, North America, the Middle East, and Australia, with the United Kingdom alone reporting more than 70 cases as of Tuesday.
These viruses are not different than they were before, but we are. For one thing, because of Covid restrictions, we have far less recently acquired immunity; as a group, more of us are vulnerable right now. And that increase in susceptibility, experts suggest, means we may experience some … wonkiness as we work toward a new post-pandemic equilibrium with the bugs that infect us.
Larger waves of illness could hit, which in some cases may bring to light problems we didn’t know these bugs triggered. Diseases could circulate at times or in places when they normally would not.
“I think we can expect some presentations to be out of the ordinary,” said Petter Brodin, a professor of pediatric immunology at Imperial College London. “Not necessarily really severe. I mean it’s not a doomsday projection. But I do think slightly out of the normal.”
Marion Koopmans, head of the department of viroscience at Erasmus Medical Center in Rotterdam, the Netherlands, said she believes we may be facing a period when it will difficult to know what to expect from the diseases that we thought we understood.
“I do think that’s possible,” Koopmans said.
This phenomenon, the disruption of normal patterns of infections, may be particularly pronounced for diseases where children play an important role in the dissemination of the bugs, she suggested.
Little kids are normally germ magnets and germ amplifiers. But their lives were profoundly altered during the pandemic. Most went for stretches of time without attending day care, or in-person school. Many had far less exposure to people outside their households, and when they did encounter others, those people may have been wearing masks.
And babies born during the pandemic may have entered the world with few antibodies passed on by their mothers in the womb, because those mothers may have been sheltered from RSV and other respiratory pathogens during their pregnancies, said Hubert Niesters, a professor of clinical virology and molecular diagnostics at the University Medical Center, in Groningen, the Netherlands.
Koopmans said a study her team did looking for antibodies in the blood of young children showed the impact of what she calls an “infection honeymoon.”
“You really see that children in the second year of the pandemic have far less antibodies to a set of common respiratory viruses. They just got less exposed,” she said.
Such factors may help explain the recent rash of unusual hepatitis cases in young children. Scientists investigating the cases think they may be caused, at least in part, by adenovirus type 41, because it has been found in a significant number of the affected children. The possibility is puzzling, because the virus hasn’t been seen to cause this type of illness in the past.
But some scientists theorize that this virus may have always been responsible for a portion of the small number of unexplained pediatric hepatitis cases that happen every year. Maybe, the thinking goes, there have been a lot more adenovirus type 41 infections over the past eight months because of increased susceptibility among children. That, in turn, could be making visible something that wasn’t spotted before.
“I think sometimes to connect the dots of rare complications of common illnesses you just need enough cases out there to start to put the pieces together,” said Kevin Messacar, a pediatric infectious diseases specialist at Children’s Hospital Colorado. “And there is some suspicion that that could be going on with the hepatitis cases.”
The pandemic-induced disruption of normal mixing patterns means that even adults haven’t been generating the levels of antibodies that would normally be acquired through the regular exposure we have to bugs, creating ever larger pools of susceptible people.
Flu experts, for instance, worry that when influenza viruses return in a serious way, a buildup of people who haven’t had a recent infection could translate into a very bad flu season.
Koopmans said some studies suggest that after a one- or two-year period in which flu transmission is low, there could be a sizeable reduction in the number of people who have flu antibodies that are at levels high enough to be considered protective. “So also, potentially, a bigger, more susceptible group in adults,” she said.
“We’re talking about endemic diseases that had a certain pattern of predictability. And that pattern in part was seasonal but in part was also driven by the size of the immune or non-immune population. And the last bit has, of course, increased,” Koopmans said.
How will this play out? All eyes will be trained this fall on children’s hospitals to see whether there will be a surge in cases of a polio-like condition called acute flaccid myelitis, or AFM, which is thought to be caused by infection with enterovirus D68.
Messacar, who is also an associate professor at the University of Colorado, has been studying AFM for the past eight years, since the first of a series of biennial waves of cases occurred in the late summer and early autumn of 2014, 2016, and 2018.
Then in 2020, nothing. Same in 2021. Does that mean the fall of 2022 could see a much higher crest of cases, because more children are potentially susceptible to enterovirus D68? We need to be prepared for that possibility, Messacar said, while stressing he doesn’t know what to expect.
“Now we have four years of children who haven’t seen that virus. We don’t know what’s going to happen. We don’t know when it comes back. But when it does come back, there are more susceptible children out there that would not be expected to have immunity,” he said. “That’s what we’re watching with a variety of different viruses.”
Thomas Clark, deputy director of the division of viral diseases at the Centers for Disease Control and Prevention, said people in public health have been fearing there could be outbreaks of vaccine-preventable diseases due to the fact that many children around the world missed getting childhood vaccinations during the pandemic.
But he said he now understands that isn’t the only way the pandemic may influence infectious diseases.
“We’re very focused on under-vaccinated children with routine childhood immunizations because it’s the set-up for introduction of measles. But then there have also been a lot of kids who haven’t gotten the usual kind of viruses they might have been exposed to.”
Clark said we may see differences in severity of some illnesses, because young children who were sheltered from bugs during the early stages of the pandemic may now catch them when they are older. Some illnesses cause more serious symptoms if they are contracted when one is older.
“Whether we will see that kind of thing over such a short period of time I think is a big question mark,” said Koopmans. “But I think it is certainly something that is worth really watching closely.”
An accumulation of susceptible people isn’t the only way the pandemic may have affected patterns of disease transmission, some experts believe.
David Heymann, who chairs an expert committee that advises the Health Emergencies Program at the World Health Organization, said the lifting of pandemic control measures could have helped fuel the spread of monkeypox in the current outbreak in Europe, North America, and beyond. Many of the monkeypox cases have been diagnosed in men who have sex with men.
After two years of limited travel, social distancing and public gatherings, people are throwing off the shackles of Covid control measures and embracing a return to pre-pandemic life. Media reports have suggest recent raves in Spain and Belgium have led to transmission of the virus among some attendees.
Heymann, who is a professor of infectious disease epidemiology at the London School of Hygiene and Tropical Medicine, mused that the monkeypox outbreak could have been smoldering at low levels in the United Kingdom or somewhere else outside of Africa for quite a while, but may have only come to public attention when international travel picked up again.
“If you look at what’s been happening in the world over the past few years, and if you look at what’s happening now, you could easily wonder if this virus entered the U.K. two to three years ago, it was transmitting below the radar screen, [with] slow chains of transmission,” said Heymann, who worked on smallpox eradication early in his career. “And then all of a sudden everything opened up and people began traveling and mixing.”
While all this could make for an unsettling time over the next couple of years, things will eventually quiet down, Brodin predicted.
“I think once you’ve infected a number of people herd immunity ensues and the virus goes away,” he said, referring to viruses in generally. “We haven’t fundamentally changed the rules of infectious diseases.”
COVID and smell loss: answers begin to emerge
Researchers are learning more about how the SARS-CoV-2 coronavirus stifles smell — and how they might revive it.
Researchers are finally making headway in understanding how the SARS-CoV-2 coronavirus causes loss of smell. And a multitude of potential treatments to tackle the condition are undergoing clinical trials, including steroids and blood plasma.
Once a tell-tale sign of COVID-19, smell disruption is becoming less common as the virus evolves. “Our inboxes are not as flooded as they used to be,” says Valentina Parma, a psychologist at the Monell Chemical Senses Center in Philadelphia, Pennsylvania, who helped field desperate inquiries from patients throughout the first two years of the pandemic.
A study published last month surveyed 616,318 people in the United States who have had COVID-19. It found that, compared with those who had been infected with the original virus, people who had contracted the Alpha variant — the first variant of concern to arise — were 50% as likely to have chemosensory disruption. This probability fell to 44% for the later Delta variant, and to 17% for the latest variant, Omicron.
But the news is not all good: a significant portion of people infected early in the pandemic still experience chemosensory effects. A 2021 study followed 100 people who had had mild cases of COVID-19 and 100 people who repeatedly tested negative. More than a year after their infections, 46% of those who had had COVID-19 still had smell problems; by contrast, just 10% of the control group had developed some smell loss, but for other reasons. Furthermore, 7% of those who had been infected still had total smell loss, or ‘anosmia’, at the end of the year. Given that more than 500 million cases of COVID-19 have been confirmed worldwide, tens of millions of people probably have lingering smell problems.
For these people, help can’t come soon enough. Simple activities such as tasting food or smelling flowers are now “really emotionally distressing”, Parma says.
A clearer picture of how SARS-CoV-2 causes this disruption should help to create better therapies for the condition. Early in the pandemic, a study showed that the virus attacks cells in the nose, called sustentacular cells, that provide nutrients and support to odor-sensing neurons.
Since then, clues have emerged about what happens to the olfactory neurons after infection. Researchers including biochemist Stavros Lomvardas at Columbia University in New York City examined people who had died from COVID-19 and found that, although their neurons were intact, they had fewer membrane-embedded receptors for detecting odor molecules than usual.
This was because the neurons’ nuclei had been scrambled. Normally, the chromosomes in these nuclei are organized into two compartments — a structure that enables the neurons to express specific odour receptors at high levels. But when the team looked at the autopsied neurons, “the nuclear architecture was unrecognizable,” Lomvardas says.
Other studies suggest why only some people experience long-term smell loss. In January, a research team reported finding a genetic mutation in people that was associated with a greater propensity for smell or taste loss. The mutation — a change to a single ‘letter’, or base, of DNA — was found in two overlapping genes, called UGT2A1 and UGT2A2. Both encode proteins that remove odor molecules from the nostrils after they have been detected. But it’s not yet clear how SARS-CoV-2 interacts with these genes.
There is also evidence of lasting changes to the brain for people with smell loss. In a study published in March, 785 people in the United Kingdom had their brains scanned twice. About 400 people became infected with COVID-19 between scans, so the scientists were able to observe structural changes. The COVID-19 survivors showed multiple changes, including markers of tissue damage in areas linked to the brain’s olfactory center. It’s not clear why this was the case, but one possibility is lack of input. “When we cut off input from the nose, the brain atrophies,” says Danielle Reed, a geneticist also at Monell. “It’s one of the clearest things we know about taste and smell.”
Treatments in testing
In the meantime, many treatments are being explored, often in small clinical trials. But it’s still early days, so the only thing that most researchers recommend for now is smell training. Patients are given samples of strong-smelling substances to sniff and try to identify, with the aim of driving the restoration of olfactory signaling. However, the method seems to work only with people who have partial smell loss, Reed says. That means it helps about one-third of people who experienced a chemosensory disruption after COVID-19, adds Parma.
To find treatments for everyone else, many researchers are exploring steroids, which reduce inflammation. COVID-19 is known to trigger extensive inflammation, which might play a part in smell disruption. So, in theory, steroids could help — but, in practice, the results have been disappointing. For instance, a 2021 study gave smell training to 100 people with post-COVID anosmia. Fifty of them also received a nasal spray with the steroid mometasone furoate, while the other 50 did not. There was no significant difference in outcome between the two groups.
Another therapeutic possibility is platelet-rich plasma; this is made from patients’ own blood and is rich in biochemicals that might induce healing. A pilot study published in 2020 followed seven patients who had platelet-rich plasma injected into their noses: five showed improvement after three months. Similarly, a preprint published in February this year followed 56 people and found that platelet-rich plasma made them more sensitive to smells. But these are “really small numbers”, says Carl Philpott, a nose and sinus specialist at the University of East Anglia, Norwich, UK. A US-based team is now launching a larger study.
Unlike COVID-19 vaccines, which were tested at unprecedented speed because of tremendous government support, treatments for post-COVID chemosensory dysfunction are plodding along. Philpott is in the early stages of a small study of vitamin A, which previous experiments have suggested could help with other forms of smell loss. “The reality is that the study will take the rest of this year to run, and it’ll take us probably to the middle of next year before we analyze the data and report it,” Philpott says. “If we find a positive benefit, our next job will be to apply for more funding to do a full stage trial.”
COVID antibody drugs have saved lives — so why aren’t they more popular?
Drugs made from antibodies are huge money-makers for some conditions — but they have gained little traction in infectious diseases, including COVID.
Arturo Casadevall watched aghast as the number of COVID-19 cases started to climb at the start of the pandemic. But he also saw scope for a solution. For decades, Casadevall, an infectious-disease researcher at Johns Hopkins Bloomberg School of Public Health in Baltimore, Maryland, has been working in the laboratory and in the clinic to unleash the potential of monoclonal antibody therapies — extremely precise drugs made up of the proteins that defend the body against invading microorganisms. With a new virus running rampant and no treatment options available, Casadevall hoped that antibodies would have their chance to shine.
The drugs rose to the occasion. By early November 2020, the US Food and Drug Administration (FDA) had issued emergency-use authorization for the first antibody to treat COVID-19, which reached patients before any vaccines or other tailored antivirals. More followed, helping to save the lives of people with COVID-19 and even staving off infection in healthy recipients. When Casadevall’s cousin came down with COVID-19 last August, Casadevall helped to lobby his cousin’s doctor to prescribe an antibody. “Antibodies need to be celebrated,” he says.
But despite the early successes, the party hasn’t started. Instead, governments and drug developers threw their weight behind vaccines, which are cheaper to make and easier to dispense; antibody drugs for COVID-19 can cost thousands of dollars a dose, compared with just a few dollars for vaccines. Globally, supply and demand for antibodies was low, and the drugs were sidelined. Even in the United States, where they’ve been used the most, they can be hard to get hold of. And as the virus started to evolve, the efficacy of the earliest antibodies waned.
Antibodies that treat cancer and immune dysfunctions are a booming, multibillion-dollar industry. But little new funding has been directed to those aimed at viruses and bacteria, and the number of infectious-disease antibodies in clinical development has flat-lined. That could be set to change: non-profit groups are hoping to support the development of antibodies as a way to prepare for future outbreaks.
Vaccines might be the ideal way to tackle a global pandemic — but they shouldn’t be the only one, says Angela Rasmussen, a virologist at the Vaccine and Infectious Disease Organization at the University of Saskatchewan in Saskatoon, Canada. “It is really crucially important that we don’t pick one horse and bet on it. We need to bet on the entire field,” she says. Antibodies have some advantages over vaccines, such as providing lasting protection in people with weakened immune systems, she says.
Antibodies will be a key solution for the next pandemic, adds Julie Gerberding, chief executive of the Foundation for the National Institutes of Health (FNIH) in Bethesda, Maryland, and former director of the US Centers for Disease Control and Prevention. “The idea of using antibodies to ward off new infectious diseases is just — to me — common sense.”
Antibodies are a pillar of the immune system. When the body encounters a viral or bacterial invader, it custom-makes these Y-shaped proteins to bind to unique markers on the invader’s surface. The two arms of the Y lock on to the offender, and the stem fires up the immune system to call for back up.
Researchers worked out how to produce monoclonal antibodies en masse some 50 years ago, by cloning the cells that make them. Ever since, drug developers have been turning them into therapies, disarming human proteins involved in conditions such as autoimmune disorders, cancer, heart disease and migraines. Adalimumab, long the world’s top-selling drug, soothes rheumatoid arthritis and other autoimmune conditions by mopping up the inflammatory protein TNF-α. Pembrolizumab, on track to overtake adalimumab’s sales, binds to a protein on the immune system’s T cells to unleash the body’s defences on cancers. Last year, the FDA approved its 100th monoclonal antibody, and these drugs collectively reap around US$150 billion in sales worldwide every year.
But despite the natural role of antibodies in deflecting pathogens, they have had few successes against infectious diseases. This is partly because specialists have prioritized the hunt for broad-spectrum drugs that can take on multiple pathogens at a time, and antibodies are suited for only a single adversary. But industry has also been deprioritizing research into infectious diseases for decades, owing to the hurdles of making money in this space — in particular, the availability of cheap generic drugs, the need to ration medicines to slow the rise of resistance and the lower purchasing power of the countries that could benefit the most.
Just a handful of the antibodies approved by the FDA target infections, including those caused by Ebola virus, respiratory syncytial virus (RSV) and the bacteria Clostridium difficile and Bacillus anthrax.
COVID-19 has put infectious-disease antibodies back in the spotlight. A front-runner was REGEN-COV — a treatment made by Regeneron Pharmaceuticals in Tarrytown, New York. The FDA authorized it for use in emergencies in late November 2020 — a month ahead of the mRNA vaccines and more than a year before bespoke antivirals made from small molecules, such as Paxlovid (a combination of nirmatrelvir and ritonavir). “The monoclonal antibody approaches were light-speed fast,” says Ann Eakin, a senior scientific officer at the US National Institute of Allergy and Infectious Diseases (NIAID) in Bethesda.
REGEN-COV comprises two antibodies — casirivimab and imdevimab — that bind to the spike protein on the surface of the SARS-CoV-2 virus, preventing it from sneaking into host cells. In adults with mild-to-moderate COVID-19 and a high risk of severe disease, the cocktail lowers the relative risk of hospitalization or death by more than 70%: the rate was 1.3% in people who received the drug, compared with 4.6% among those who did not.
Antibody drugs can also prevent infection, both in people who have recently been exposed to the SARS-CoV-2 virus and in those who don’t respond well to vaccines. The antibody cocktail Evusheld (tixagevimab and cilgavimab), developed by AstraZeneca in Cambridge, UK, showcases these drugs’ vaccine-like capabilities: it reduces the relative risk of developing COVID-19 by more than 75% in elderly people and those with compromised immune systems, who often do not respond well to vaccines. A single dose provides at least 6 months of protection, and possibly up to 12. Last December, Evusheld became the first antibody therapy to secure FDA authorization for pre-exposure prevention of COVID-19 in people with compromised immune systems. Evusheld is also effective as a treatment, although it has not been authorized for that use.
Of all the COVID-19 antibodies, REGEN-COV has been the most widely used: the United States has administered around two million doses. It is also the most profitable, with sales of US$5.8 billion in the United States and a further $1.7 billion in the rest of the world (where it is sold by the Swiss drug firm Roche as Ronapreve). “Before the pandemic, most doctors and patients did not know a lot about therapeutic antibodies in infectious diseases,” says Regeneron’s senior vice-president, Christos Kyratsous. “We built a lot of awareness.”
But globally, availability is patchy. The United Kingdom has administered just 33,000 doses. Access to the drugs in middle- and low-income countries is almost non-existent, according to disclosed antibody purchases.
Antibodies also have an Achilles heel. Because they are picky about their targets, they are easily out-manoeuvred by rapidly evolving viruses. “Pathogens change a couple of amino acids and the antibodies no longer bind,” says Casadevall.
The first antibody to receive FDA authorization — bamlanivimab, made by Lilly in Indianapolis, Indiana — was outflanked by the virus in five months. The REGEN-COV cocktail fared better, and was used in the United States for around 14 months, helping to fill the gap in treatment options there until antivirals arrived. But its efficacy faltered with Omicron and its use was restricted. The Evusheld combination remains effective against current variants.
For James Crowe, a viral immunologist at Vanderbilt University in Nashville, Tennessee, and discoverer of the antibodies in Evusheld, such data show that two-antibody cocktails that restrict a pathogen’s escape routes are the best way forward. As researchers become better mixologists, their concoctions will last even longer against both COVID-19 and other infectious diseases, he says.
Others contend that single antibodies — if they are designed to hit the target at the right spot — might yet win out.
When COVID-19 struck, Regeneron, AstraZeneca and other antibody developers prioritized the candidates that packed the biggest punch, with the strongest ability to neutralize the virus. Researchers then combined the best performers to make the final product. But others went for staying power, focusing on regions of the spike protein that mutate more slowly. These candidates might be less potent in animal models, but they stand a better chance of fighting off future variants of SARS-CoV-2 and perhaps even related coronaviruses, says Herbert Virgin, chief scientific officer at Vir Biotechnology in San Francisco, California. His team used this approach to discover the antibody sotrovimab, and partnered with the UK drug firm GlaxoSmithKline in London to develop it; another partnership with a similar goal, between Lilly and AbCellera in Vancouver, Canada, yielded bebtelovimab.
Bebtelovimab is now the only antibody recommended as a treatment in the United States, and only when antivirals are unavailable. Sotrovimab is the only one in use in the United Kingdom.
These ‘broadly neutralizing’ antibodies are the future, argues Virgin. “If we had a few of those on the shelf, we might not have to isolate new antibodies when the next pandemic arises,” he says.
The idea is not new; drug developers have been hunting for such antibodies for other viruses for decades. They have tested at least a dozen candidates against HIV in clinical trials with little success, although one study showed that a two-antibody cocktail could suppress HIV levels in a subset of people. Lasting efficacy for antibodies against SARS-CoV-2 could buoy hopes of victory against other viruses, too.
Virgin hopes that research on COVID-19 antibodies will translate into better drugs for other diseases. Vir is now tweaking sotrovimab to supercharge its ability to put the immune system into attack mode. This kind of strategy could make antibodies for other disorders such as cancer more potent — but risks sending the immune system into overdrive. If Vir can prove the approach is safe with viral targets such as SARS-CoV-2, drug developers might be tempted to use similar strategies to set the immune system on cancer cells.
Despite the clinical potential of infectious-disease antibodies, the pandemic exposed the difficulty of getting them to the people who need them. “There are the scientific challenges, and then there are the policy challenges. I’m glad I work on the former,” says Mark Esser, vice-president of microbial sciences at AstraZeneca.
Health-care systems have struggled to distribute COVID-19 antibodies effectively and equitably, even more so than they did with vaccines and antiviral medicines such as Paxlovid. Not only do these drugs need to be given early in the course of infection for best effect, but the first COVID-19 antibodies were also best delivered by intravenous drip. This created diagnostic, infrastructural, staffing and other bottlenecks.
Antibodies also tend to cost more than do antivirals and vaccines — around $2,100 per dose of REGEN-COV, for example, versus up to $530 for Paxlovid or $20 for the mRNA vaccine Comirnaty, which is made by Pfizer, in New York City, and BioNTech in Mainz, Germany.
But more broadly, infectious diseases have long been a losing ticket for the pharmaceutical industry. One of the problems is that no health system or pharmaceutical company wants to spend money on drugs that are used infrequently, only as last resorts. COVID-19 has provided an unprecedented windfall in terms of infectious diseases for some, but it remains hard to build a company on once-in-a-generation pandemics.
As business returns to normal, companies will keep prioritizing the most profitable drug-development opportunities. A few viruses could fit the bill. Even before the pandemic, Vir was testing antibody drugs to treat influenza and hepatitis B virus, which infects the liver. Gilead Sciences in Foster City, California, is developing the two-antibody cocktail for HIV that has shown some promise. And AstraZeneca hopes to soon secure approval for a long-acting antibody called nirsevimab, to protect newborns against RSV infection.
There are opportunities for infectious-disease antibodies in settings where “vaccines won’t work or won’t work well”, says Esser.
The task of preparing a drug cabinet to be ready for future pandemics is likely to fall to governments and charities, adds Crowe. To this end, he has founded the AHEAD 100 initiative, a non-profit collaboration to develop and stockpile 100 monoclonal antibodies that can protect against 25 high-risk virus families and hopefully quell would-be pandemics. He puts the price tag for this work at $2.5 billion.
The Coalition for Epidemic Preparedness Innovations (CEPI) in Oslo, another non-profit group that is investing billions of dollars into vaccines for pandemics, has also added antibodies to its remit. It could soon start funding work on antibodies against four priority pathogens, which are yet to be identified. “We are at a major historical tipping point, in which antibodies are going to become one of the principal tools that we use to manage infectious diseases,” says Crowe.
Eakin expects that it is just a matter of time before infectious-disease antibodies get more financial support. So far, public and private funders have prioritized vaccine platforms; in May, NIAID invested $577 million in small-molecule antivirals, but only because they were so much slower to progress through the pipeline than were vaccines and antibodies. Antibodies are for now stuck in the neglected middle, but Eakin doesn’t think they will stay there.
Gerberding, too, hopes that more funding is coming for infectious-disease antibodies — as well as for other pillars of pandemic preparedness. “We’re just scratching the surface of what we have the capability of doing, but we don’t want to pay the bill. If we haven’t learnt yet from COVID that paying the bill would have been worth it, I don’t know what it’s going to take.”
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