Pandemics In History

I have written several articles on the coronavirus and on masks and healthcare issues. A series of links have been provided at the bottom of this article for your convenience. This article will, however address a different aspect of the virus or on healthcare issues in general.

I came across a posting in, entitled “Pandemics That Changed History.” The article was so well done, that I can’t improve on it, so I have included it in its entirety below. I have done so, because I feel that the more information people have access to the better. I want to show that we have survived many pandemics throughout our history, and we will survive this one. As long as we don’t give up and remain strong, we will overcome this pandemic. At least we know how to fight it. Our ancestors were not as lucky.

In the realm of infectious diseases, a pandemic is the worst case scenario. When an epidemic spreads beyond a country’s borders, that’s when the disease officially becomes a pandemic.

Communicable diseases existed during humankind’s hunter-gatherer days, but the shift to agrarian life 10,000 years ago created communities that made epidemics more possible. Malaria, tuberculosis, leprosy, influenzasmallpox and others first appeared during this period.

The more civilized humans became, building cities and forging trade routes to connect with other cities, and waging wars with them, the more likely pandemics became. See a timeline below of pandemics that, in ravaging human populations, changed history.

430 B.C.: Athens

The earliest recorded pandemic happened during the Peloponnesian War. After the disease passed through Libya, Ethiopia and Egypt, it crossed the Athenian walls as the Spartans laid siege. As much as two-thirds of the population died.

The symptoms included fever, thirst, bloody throat and tongue, red skin and lesions. The disease, suspected to have been typhoid fever, weakened the Athenians significantly and was a significant factor in their defeat by the Spartans.

165 A.D.: Antonine Plague

The Antonine plague was possibly an early appearance of smallpox that began with the Huns. The Huns then infected the Germans, who passed it to the Romans and then returning troops spread it throughout the Roman empire. Symptoms included fever, sore throat, diarrhea and, if the patient lived long enough, pus-filled sores. This plague continued until about 180 A.D., claiming Emperor Marcus Aurelius as one of its victims.

250 A.D.: Cyprian Plague

Named after the first known victim, the Christian bishop of Carthage, the Cyprian plague entailed diarrhea, vomiting, throat ulcers, fever and gangrenous hands and feet.

City dwellers fled to the country to escape infection but instead spread the disease further. Possibly starting in Ethiopia, it passed through Northern Africa, into Rome, then onto Egypt and northward.

There were recurring outbreaks over the next three centuries. In 444 A.D., it hit Britain and obstructed defense efforts against the Picts and the Scots, causing the British to seek help from the Saxons, who would soon control the island.

541 A.D.: Justinian Plague

First appearing in Egypt, the Justinian plague spread through Palestine and the Byzantine Empire, and then throughout the Mediterranean.

The plague changed the course of the empire, squelching Emperor Justinian’s plans to bring the Roman Empire back together and causing massive economic struggle. It is also credited with creating an apocalyptic atmosphere that spurred the rapid spread of Christianity.

Recurrences over the next two centuries eventually killed about 50 million people, 26 percent of the world population. It is believed to be the first significant appearance of the bubonic plague, which features enlarged lymphatic gland and is carried by rats and spread by fleas.

11th Century: Leprosy

Though it had been around for ages, leprosy grew into a pandemic in Europe in the Middle Ages, resulting in the building of numerous leprosy-focused hospitals to accommodate the vast number of victims.

A slow-developing bacterial disease that causes sores and deformities, leprosy was believed to be a punishment from God that ran in families. This belief led to moral judgments and ostracization of victims. Now known as Hansen’s disease, it still afflicts tens of thousands of people a year and can be fatal if not treated with antibiotics.

1350: The Black Death

Responsible for the death of one-third of the world population, this second large outbreak of the bubonic plague possibly started in Asia and moved west in caravans. Entering through Sicily in 1347 A.D. when plague sufferers arrived in the port of Messina, it spread throughout Europe rapidly. Dead bodies became so prevalent that many remained rotting on the ground and created a constant stench in cities.

England and France were so incapacitated by the plague that the countries called a truce to their war. The British feudal system collapsed when the plague changed economic circumstances and demographics. Ravaging populations in Greenland, Vikings lost the strength to wage battle against native populations, and their exploration of North America halted.

1492: The Columbian Exchange

Following the arrival of the Spanish in the Caribbean, diseases such as smallpox, measles and bubonic plague were passed along to the native populations by the Europeans. With no previous exposure, these diseases devastated indigenous people, with as many as 90 percent dying throughout the north and south continents.

Upon arrival on the island of Hispaniola, Christopher Columbus encountered the Taino people, population 60,000. By 1548, the population stood at less than 500. This scenario repeated itself throughout the Americas.

In 1520, the Aztec Empire was destroyed by a smallpox infection. The disease killed many of its victims and incapacitated others. It weakened the population so they were unable to resist Spanish colonizers and left farmers unable to produce needed crops.

Research in 2019 even concluded that the deaths of some 56 million Native Americans in the 16th and 17th centuries, largely through disease, may have altered Earth’s climate as vegetation growth on previously tilled land drew more CO2 from the atmosphere and caused a cooling event.

1665: The Great Plague of London

In another devastating appearance, the bubonic plague led to the deaths of 20 percent of London’s population. As human death tolls mounted and mass graves appeared, hundreds of thousands of cats and dogs were slaughtered as the possible cause and the disease spread through ports along the Thames. The worst of the outbreak tapered off in the fall of 1666, around the same time as another destructive event—the Great Fire of London.

1817: First Cholera Pandemic

The first of seven cholera pandemics over the next 150 years, this wave of the small intestine infection originated in Russia, where one million people died. Spreading through feces-infected water and food, the bacterium was passed along to British soldiers who brought it to India where millions more died. The reach of the British Empire and its navy spread cholera to Spain, Africa, Indonesia, China, Japan, Italy, Germany and America, where it killed 150,000 people. A vaccine was created in 1885, but pandemics continued.

1855: The Third Plague Pandemic

Starting in China and moving to India and Hong Kong, the bubonic plague claimed 15 million victims. Initially spread by fleas during a mining boom in Yunnan, the plague is considered a factor in the Parthay rebellion and the Taiping rebellion. India faced the most substantial casualties, and the epidemic was used as an excuse for repressive policies that sparked some revolt against the British. The pandemic was considered active until 1960 when cases dropped below a couple hundred.

1875: Fiji Measles Pandemic

After Fiji ceded to the British Empire, a royal party visited Australia as a gift from Queen Victoria. Arriving during a measles outbreak, the royal party brought the disease back to their island, and it was spread further by the tribal heads and police who met with them upon their return.

Spreading quickly, the island was littered with corpses that were scavenged by wild animals, and entire villages died and were burned down, sometimes with the sick trapped inside the fires. One-third of Fiji’s population, a total of 40,000 people, died.

1889: Russian Flu

The first significant flu pandemic started in Siberia and Kazakhstan, traveled to Moscow, and made its way into Finland and then Poland, where it moved into the rest of Europe. By the following year, it had crossed the ocean into North America and Africa. By the end of 1890, 360,000 had died.

1918: Spanish Flu

The avian-borne flu that resulted in 50 million deaths worldwide, the 1918 flu was first observed in Europe, the United States and parts of Asia before swiftly spreading around the world. At the time, there were no effective drugs or vaccines to treat this killer flu strain. Wire service reports of a flu outbreak in Madrid in the spring of 1918 led to the pandemic being called the “Spanish flu.”

By October, hundreds of thousands of Americans died and body storage scarcity hit crisis level. But the flu threat disappeared in the summer of 1919 when most of the infected had either developed immunities or died.

1957: Asian flu

Starting in Hong Kong and spreading throughout China and then into the United States, the Asian flu became widespread in England where, over six months, 14,000 people died. A second wave followed in early 1958, causing an estimated total of about 1.1 million deaths globally, with 116,000 deaths in the United States alone. A vaccine was developed, effectively containing the pandemic.

1981: HIV/AIDS

First identified in 1981, AIDS destroys a person’s immune system, resulting in eventual death by diseases that the body would usually fight off. Those infected by the HIV virus encounter fever, headache, and enlarged lymph nodes upon infection. When symptoms subside, carriers become highly infectious through blood and genital fluid, and the disease destroys t-cells.

AIDS was first observed in American gay communities but is believed to have developed from a chimpanzee virus from West Africa in the 1920s. The disease, which spreads through certain body fluids, moved to Haiti in the 1960s, and then New York and San Francisco in the 1970s.

Treatments have been developed to slow the progress of the disease, but 35 million people worldwide have died of AIDS since its discovery, and a cure is yet to be found.

2003: SARS

First identified in 2003 after several months of cases, Severe Acute Respiratory Syndrome is believed to have possibly started with bats, spread to cats and then to humans in China, followed by 26 other countries, infecting 8,096 people, with 774 deaths.

SARS is characterized by respiratory problems, dry cough, fever and head and body aches and is spread through respiratory droplets from coughs and sneezes.

Quarantine efforts proved effective and by July, the virus was contained and hasn’t reappeared since. China was criticized for trying to suppress information about the virus at the beginning of the outbreak.

SARS was seen by global health professionals as a wake-up call to improve outbreak responses, and lessons from the pandemic were used to keep diseases like H1N1, Ebola and Zika under control.

2019: COVID-19

On March 11, 2020, the World Health Organization announced that the COVID-19 virus was officially a pandemic after barreling through 114 countries in three months and infecting over 118,000 people. And the spread wasn’t anywhere near finished.

COVID-19 is caused by a novel coronavirus—a new coronavirus strain that has not been previously found in people. Symptoms include respiratory problems, fever and cough, and can lead to pneumonia and death. Like SARS, it’s spread through droplets from sneezes.

The first reported case in China appeared November 17, 2019, in the Hubei Province, but went unrecognized. Eight more cases appeared in December with researchers pointing to an unknown virus. 

Many learned about COVID-19 when ophthalmologist Dr. Li Wenliang defied government orders and released safety information to other doctors. The following day, China informed WHO and charged Li with a crime. Li died from COVID-19 just over a month later.

Without a vaccine available, the virus spread beyond Chinese borders to nearly every country in the world. By December 2020, it had infected more than 75 million people and led to more than 1.6 million deaths worldwide. The number of new cases was growing faster than ever, with more than 500,000 reported each day on average.

Many people are against vaccinations, and that is their right to feel this way. However, I can’t but feel that they are acting out ignorance. Widespread vaccination has helped decrease or virtually eliminate many dangerous and deadly diseases in the United States. Yet because vaccines have been so effective at removing threats, it’s sometimes difficult to appreciate just how significant they have been to public health.

Here are four major diseases that you may have forgotten about (or downplayed) thanks to how effective vaccines have been at mitigating or eliminating them. (1) Smallpox, (2) Rabies, (4) The Flu.

Smallpox is the only human disease that has been globally eradicated through vaccines. It’s also responsible for the first known vaccine, created by the English physician Edward Jenner in 1796. After observing that milkmaids who caught cowpox (a milder disease) seemed to gain immunity to smallpox, Jenner inoculated an eight-year-old boy using a milkmaid’s cowpox lesion. He then exposed the boy to smallpox, and when the boy didn’t develop any symptoms of the deadly disease, Jenner realized he’d developed a way to prevent it.

Rabies has played a large role in American film and literature—think Old YellerTo Kill a Mockingbird and Their Eyes Were Watching God. But the deadly disease, which causes erratic behavior, is no longer a major threat in the United States because of vaccines.

In this case, most of the vaccines that have helped save human lives aren’t used on humans—they’re used on other animals that can carry the disease and infect humans by biting them. State rabies programs have guidelines for vaccinating pets and wildlife and tracking animals that might have rabies. Any human who is bitten by an animal, regardless of whether the animal has been vaccinated, must go to a doctor or hospital to receive a rabies vaccine.

Polio was once one of the most feared childhood diseases in the U.S. The viral infection can cause temporary or permanent paralysis, as it did with wheelchair-user Franklin D. Roosevelt. This paralysis could stop a person’s body from breathing on its own, which is why so many infected people had to be placed in an “iron lung.” By the late 1940s, it was disabling more than 35,000 Americans each year. The number of U.S. polio cases peaked in 1952, when it caused 57,879 infections and 3,145 deaths.

During the 1954 trials for Jonas Salk’s polio vaccine, parents flocked to sign their children up to get the shot. As a result, 623,972 children received the vaccine or a placebo. The trials showed the vaccine was 80 to 90 percent effective at preventing polio. Thanks to the continued vaccination of children through today, no polio cases have originated in the United States since 1979. However, polio has not been eradicated, and remains a health threat in Afghanistan and Pakistan.

During the early spread of COVID-19, there was a lot of discussion about whether the infectious disease was serious, or “like the flu”—i.e., not a threat. However, influenza remains a deadly disease that has caused previous pandemics and has the potential to cause future ones as well (Najera speculates the next flu pandemic will happen “sooner rather than later”).


Man is without a doubt the apex predator in this planet, with technology we can extinguish any life form or species, and we have driven countless species into extinction through our careless predation. However, we have been unable to eradicate viruses. we have managed to eliminate a few with vaccinations, but for the most part the vast majority of them still exist and routinely kick our asses. I believe viruses are the worlds way of population control. It seems the greater the incursion into nature, the harder nature fights back. It is humbling to think that something so small can bring civilization to its knees.

Viruses are self limiting, they can only produce and exist in a host. The definition of a virus is a submicroscopic infectious agent that replicates only inside the living cells of an organism. They are also called obligate parasites for the same reason. As such they are simplistic – so simple , in fact, that they don’t satisfy all the criteria to be considered alive. Viruses cannot synthesize adenosine triphosphate, a critical molecule used for carrying energy. They likewise do not posses the molecular equipment to perform translation, the process that uses information from the genetic code called RNA to synthesize the proteins, which are the workhorses of cellular life. Viruses infect all types of life forms, from animals and plants to microorganisms, including bacteria and archaea. If the host species are totally killed off, the virus dies with it. So for a virus to proliferate, it has to be easily spread and to also not be so deadly that id kills its host before it spreads. It seems viruses have a better understanding of nature than do people. People have been compared to a cancer, because a cancer has not shut off switch. Healthy cells stop growing when they reach a boundary, while cancers spread uncontrollably. Humans behave in much the same way. So the question is who is the apex species in this planet?

Resources, “Pandemics That Changed History,” By editors;, “Did bubonic plague really cause the Black Death?” By Debora Mackenzie;, “‘Spillover’ diseases are emerging faster than ever before—thanks to humans: History is pockmarked with the scars of past zoonotic outbreaks. What have we learned, why are they increasing, and what can we do to avoid them?” BY SHARON GUYNUP;, “‘Historic moment’: Why the WHO endorsed the first malaria vaccine: The move marks the start of a highly anticipated rollout for this type of vaccine, which experts say could boost the health of millions of at-risk children.” BY MICHAEL GRESHKO; How it works, bookzine series. “Virus;”


Where do Viruses Come From?

(Update 10/11/2021)

How did viruses evolve? Were they once fully equipped microorganisms that shed their molecular dead weight and became parasites, or did they begin as just genetic code and gain a few fancy tools that helped them ensure their own replication? Or did viruses first evolve before even single-celled organisms, and those that persist today ae mere relics of an ancient emergence of life?

The Precursor Hypothesis

Genetic code is the basis of life on earth. It is, as far as we understand, the first organic molecule capable of carrying swathes of chemical instructions and so underpins all life. Genetic code is made up of nucleic acids, DNA and RNA. In complex life, DNA is the first transcribed into RNA, which then relays the chemical instructions to molecules called ribosomes that form proteins. In this setup, RNA is the intermediate component, but it’s now believed that RNA was the first nucleic acid to exist at the origin of life. Scientists have also identified a group of RNA molecules known as ribozymes that can catalyze chemical reactions – a job principally performed by proteins. Therefore, at the origin of life, the very first entities may not have needed DNA or proteins at all in order to replicate.

If such self-replicating units existed prior to the evolution of the very first cells, they may have been primed to infect these cells once they appeared. Therefore, the parasitic role of the virus may have been established as soon as they first contacted cellular life. Some viruses still solely use RNA as their genetic code and may be the closest descendants to their ancient parasitic forerunners.

The Regression Hypothesis

Viruses that exist today all gain by damaging their hosts, but it may not have always been his way. Many species in nature exist in symbiotic relationships, where both parties can benefit from the other’s presence. An example of this would be the exchange of nutrients between fungi and plant roots in the soil, or African birds such as piapiacs that eat lice from the backs of large land mammals. Viruses may have once enjoyed such a mutually beneficial relationship with another organism. Over time, however, the viruses hat decided to lose their own molecular machinery in favor of using their partner’s could have gained an adaptive advantage. Making molecular apparatus is costly for a cell; it requires lots of genetic instructions, lots of energy and lots of resources. The viruses that accidentally lost their once essential pieces of kit may have found that they could persist much better by instead using another’s tools.

Although all known viruses today are obligate parasites, some larger viruses offer support for the regression hypothesis by resembling self-sufficient ancestors. The Mimivirus, for example, is a behemoth among viruses. It is gargantuan in both how much genetic code it carries and simply how large it is. Adeno-associated viruses can be absolutely miniscule, measuring just 20 nanometers in diameter. They also have tiny lengths of genetic code containing just 4,5000 nucleotide bases, In stark contrast, the giant Mimivirus can measure 500 nanometers and boast whopping genetic code of 1.2 million nucleotide bases. Not only does the size of the Mimivrus resemble fully living microbes, its DNA also contains instructions for an an incomplete set of proteins for metabolism and translation. Larger viruses also tend to depend on their hosts less than their smaller counterparts, with some being able to convert their NA into RNA without direct input from the host. It has been proposed that these larger viruses, in particular the Mimivirus, could be examples of viruses that have retained many elements of what ancestors of all viruses once possessed.

The Progression Hypothesis

Viruses straddle the boundary of what biologists consider to be life. On the one hand, they cannot regulate their internal state or indeed carry out any metabolic processes, and independently they don’t respond to stimuli. On the other hand, they do reproduce. This Latter attribute is hugely important , because the ability to pass on genetic material is all that’s needed for evolutionary processes to work. So the origin of viruses may not have arisen from an independent biological entity at all but from fragments of code that became immensely effective at facilitating its own replication.

Transposable genetic elements are segments of genetic code that can move position within DNA. They are sometimes referred to as jumping genes as they ho to either anther location along the DNA strand or they jump to another DNA strand entirely. The human genome is packed full full of a form of jumping genes called retrotransposons. They can carry genetic instructions that allow them to be both copied and then pasted into new DNA, enabling them to snugly integrated into the genetic fabric of a new cell. A family of viruses called retroviruses operates in a highly similar way, such as Human Immunodeficiency Viruses (HIV), which effectively infect and then integrate into their host’s DNA. Proponents of the progression hypothesis recognize the familiarity between virus-like retrotransposons and retroviruses. What if a chance event gifted a retrotransposon new genetic material that allowed it to encase itself in a protein shell and easily migrate to new cells? The genetic code would not be alive, but it would be able to flourish and perhaps, evolve into the viruses that exist in the world today.


Th regression hypothesis argues that viruses are simple entities because they lost most of the molecular machinery needed to maintain life. The progression hypothesis instead argues the first viruses never had this machinery to begin with but instead evolved from an assembled set of components needed for migrating and replicating genetic code. The precursor hypothesis, in contrast, suggests viruses lack complex cellular apparatus because they’re remnants of an ancestral form of life evolved before these units appeared.

Viruses are incredibly diverse entities. Some are tiny, others large; some possess DNA and others RNA. Depending on what group of viruses we zoom in on, certain theories seem more plausible. The gargantuan Mimivirus and other larger viruses like the Poxvirus are indicative of the regression hypothesis, retroviruses such as HIV the progressive hypothesis, and other RNA viruses the precursor hypothesis. One or all of these hypotheses may be correct. It is possible that rather originating from a universal ancestor, viruses evolved multiple times independently. If this is the case, their shared features may be a product of a phenomenon known as convergent evolution, where natural selection causes different organisms to acquire the same trait. An example of this would be wings. Birds and insects haven’t shared a common ancestor for millions of years, yet both converged on the same trait of flight.

If viruses in fact have multiple origins, then they my have picked up similar features through shared lifestyles of being obligate intracellular parasites. Alternatively, an as yet unconsidered hypothesis may hold the answer, and only by continuing the search to discover new viruses will we discover the true origin of these fascinating biological entities.

Did bubonic plague really cause the Black Death?

Everyone thinks the Black Death was caused by bubonic plague. But they could be wrong – and we need to find the real culprit before it strikes again

THE DISEASE that spread like wildfire through Europe between 1347 and 1351 is still the most violent epidemic in recorded history. It killed at least a third of the population, more than 25 million people. Victims first suffered pain, fever and boils, then swollen lymph nodes and blotches on the skin. After that they vomited blood and died within three days. The survivors called it the Great Pestilence. Victorian scientists dubbed it the Black Death.

As far as most people are concerned, the Black Death was bubonic plague, Yersinia pestis, a flea-borne bacterial disease of rodents that jumped to humans. But two epidemiologists from Liverpool University say we’ve got it all wrong. In Biology of Plagues, a book released earlier this year, they effectively demolish the bubonic plague theory. “If you look at how the Black Death spread,” says Susan Scott, one of the authors, “one of the least likely diseases to have caused it is bubonic plague.” If Scott and co-author Christopher Duncan are right, the world would do well to listen.

Whatever pathogen caused the Black Death appears to have ravaged Europe several times during the past two millennia, and it could resurface again. If we knew what it really was, we could prepare for it. “It’s always important to re-evaluate these questions so we are not taken by surprise,” says Steve Morse, an expert on emerging viral diseases at Columbia University in New York. Yet few experts in infectious diseases have even read the book, let alone taken its ideas seriously. New Scientist has, and it looks to us as though Scott and Duncan are on to something.

The idea that the Black Death was bubonic plague dates back to the late 19th century, when Alexandre Yersin, a French bacteriologist, unravelled the complex biology of bubonic plague. He noted that the disease shared a key feature with the Black Death: the bubo, a dark, painful, swollen lymph gland usually in the armpit or groin. Even though buboes also occur in other diseases, he decided the two were the same, even naming the bacterium pestis after the Great Pestilence.

But the theory is riddled with glaring flaws, say Scott and Duncan. First of all, bubonic plague is intimately associated with rodents and the fleas they carry. But the Black Death’s pattern of spread doesn’t fit a rat and flea-borne disease. It raced across the Alps and through northern Europe at temperatures too cold for fleas to hatch, and swept from Marseilles to Paris at four kilometres a day – -far faster than a rat could travel. Moreover, the rats necessary to spread the disease simply were not there. The only rat in Europe in the Middle Ages was the black rat, Rattus rattus, which stays close to human habitation. Yet the Black Death jumped across great tracts of open country-up to 300 kilometres between towns in France-in only a few days with no intermediate outbreaks. “Iceland had no rats at all,” notes Duncan, “but the Black Death was reported there too.”

In contrast, bubonic plague spreads, as rats do, slowly and sporadically. In 1907, the British Plague Commission in India reported an outbreak that took six months to move 300 feet. After bubonic plague arrived in South Africa in 1899, it moved inland at just 20 kilometres a year, even with steam trains to help.

The disease that caused the Black Death stayed in Europe until 1666. During its 300-year reign, Scott and Duncan have found records of outbreaks that occurred somewhere in France virtually every year. Every few years, these outbreaks spawned epidemics that ravaged the rest of Europe. For Yersinia to do this, it would have to become established in a population of rodents that are resistant to the disease. It couldn’t have been rats, because the plague bacterium kills them-along with all other European rodents. As a result, Europe, along with Australia and Antarctica, remain the only regions of the world where bubonic plague has never settled. So, once again, the Black Death behaved in a way plague simply cannot.

Nor is bubonic plague contagious enough to have been the Black Death. The Black Death killed at least a third of the population wherever it hit, sometimes more. But when bubonic plague hit India in the 19th century, fewer than 2 per cent of the people in affected towns died. And when plague invaded southern Africa, South America and the south-western US, it didn’t trigger a massive epidemic.

The most obvious problem with the plague theory is that, unlike bubonic plague, the Black Death obviously spread directly from person to person. People in the thick of the epidemic recognised this, and Scott and Duncan proved they were right by tracing the anatomy of outbreaks, person by person, using English burial records from the 16th century. These records, which detail all deaths from the pestilence by order of Elizabeth I, clearly show the disease spreading from one person to their neighbours and relatives, separated by an incubation period of 20 to 30 days.

The details tally perfectly with a disease that kills about 37 days after infection. For the first 10 to 12 days, you weren’t infectious. Then for 20 to 22 days, you were. You only knew you were infected when you fell ill, for the final five days or less-but by then you had been infecting people unknowingly for weeks. Europeans at the time clearly knew the disease had a long, infectious incubation period, because they rapidly imposed measures to isolate potential carriers. For example, they stopped anyone arriving on a ship from disembarking for 40 days, or quarantina in Italian – -the origin of the word quarantine.

Telltale timing

Epidemiologists know that diseases with a long incubation time create outbreaks that last months. From 14th-century ecclesiastical records, Scott and Duncan estimate that outbreaks of the Black Death in a given town or diocese typically lasted 8 or 9 months. That, plus the delay between waves of cases, is the fingerprint of the disease across Europe over seasons and centuries, they say. The pair found exactly the same pattern in 17th-century outbreaks in Florence, Milan and a dozen towns across England, including London, Colchester, Newcastle, Manchester and Eyam in Derbyshire. In 1665, the inhabitants of Eyam selflessly confined themselves to the village. A third of them died, but they kept the disease from reaching other towns. This would not have worked if the carriers were rats.

Despite the force of their argument, Scott and Duncan have yet to convince their colleagues. None of the experts that New Scientist spoke to had read their book, and a summary of its ideas provoked reactions that range from polite interest to outright dismissal. Some of Scott’s colleagues, for example, have scoffed that “everyone knows the Black Death was bubonic plague”.

“I doubt you can say plague was not involved in the Black Death, though there may have been other diseases too,” says Elisabeth Carniel, a bubonic plague expert at the Pasteur Institute in Paris. “But I haven’t had time to read the book.” Carniel suggests that fleas could have spread the Black Death directly between people. Human fleas can keep it in their guts for a few weeks, leading to a delay in spread. But this would be unlikely to have happened the same way every time.

Moreover, people with enough Yersinia in their blood for a flea to pick it up are already very sick. They would only be able to pass their infection on in this way for a very short time-and whoever the flea bit would also sicken within a week, the incubation time of Yersinia. This does not fit the pattern documented by Scott and Duncan. Neither would an extra-virulent Yersinia, which would still depend on rats.

There have been several other ingenious attempts to save the Yersinia theory as inconsistencies have emerged. Many fall back on pneumonic plague, a variant form of Yersinia infection. This can occur in the later stages of bubonic plague, when the bacteria sometimes proliferate in the lungs and can be coughed out, and inhaled by people nearby. Untreated pneumonic plague is invariably fatal and can spread directly from person to person.

But not far, and not for long-plague only becomes pneumonic when the patient is practically at death’s door. “It is simply impossible that people sick enough to have developed the pneumonic form of the disease could have travelled far,” says Scott. Yet the Black Death typically jumped between towns in the time a healthy human took to travel. Also, pneumonic plague kills quickly-within six days, usually less. With such a short infectious period, local outbreaks of pneumonic plague end much sooner than 8 or 9 months, notes Scott. Rats and fleas can restart them, but then the disease is back to spreading slowly and sporadically like flea-borne diseases. Moreover, pneumonic plague lacks the one thing that links Yersinia to the Black Death: buboes.

If the Black Death wasn’t bubonic plague, then what was it? Possibly-and ominously-it may have been a virus. The evidence comes from a mutant protein on the surface of certain white blood cells. The protein, CCR5, normally acts as a receptor for the immune signalling molecules called chemokines, which help control inflammation. The AIDS virus and the poxvirus that causes myxomatosis in rabbits also use CCR5 as a docking port to enter and kill immune cells.

In 1998, a team led by Stephen O’Brien of the US National Cancer Institute analysed a mutant form of CCR5 that gives some protection against HIV. From its pattern of occurrence in the population, they think it arose in north-eastern Europe some 2000 years ago-and around 700 years ago, something happened to boost its incidence from 1 in 40,000 Europeans to 1 in 5. “It had to have been a breathtaking selective pressure to jack it up that high,” says O’Brien. The only plausible explanation, he thinks, is that the mutation helped its carriers survive the Black Death. In fact, say Scott and Duncan, Europeans did seem to grow more resistant to the disease between the 14th and 17th centuries.

Yersinia, too, enters and kills immune cells when it causes disease. But when O’Brien’s team pitted Yersinia against blood cells from people with and without the mutation, they found no dramatic difference. “The results were equivocal,” says O’Brien. “We don’t know if the mutation protected or not.” Further experiments are under way. Similar mutations occur elsewhere in the world, but at nowhere near the high frequency of the European mutant. This suggests that pathogens such as smallpox exerted some selective force, but nothing like whatever happened in Europe, says O’Brien.

The association between CCR5 and viruses suggests that the Black Death was a virus too. Its sudden emergence, and equally sudden disappearance after the Great Plague of London in 1666, also argue for a viral cause. Like the deadly flu of 1918, viruses can sometimes mutate into killers, and then disappear.

But what sort of virus was the Black Death? Scott and Duncan suggest a haemorrhagic filovirus such as Ebola, since the one consistent symptom was bleeding. In fact they think “haemorrhagic plague” would be a good new name for the disease.

They are not the first to blame Ebola for an ancient plague. Scientists and classicists in San Diego reported in 1996 that the symptoms of the plague of Athens around 430 BC, described by Thucydides, are remarkably similar to Ebola, including a distinctive retching or hiccupping. Apart from that, many of the symptoms of that plague- – and one in Constantinople in AD 540 – -were similar to the Black Death.

Of course, the filoviruses we know about are relatively hard to catch, with an incubation period of a week or less, not three weeks or more. But there are other haemorrhagic viruses: Lassa fever in Africa is fairly contagious, and incubates for up to three weeks. Eurasian hantaviruses can incubate for up to 42 days, but are not usually directly contagious between people. Both can be as deadly as the Black Death.

Out of Africa

Perhaps we can narrow the search to Africa. Europeans first recorded the Black Death in Sicily in 1347. The Sicilians blamed it on Genoese galleys that arrived from Crimea just as the illness exploded. But the long incubation period means the infection must have arrived earlier. Scott suspects it initially came from Africa, just a short hop away from Sicily. That continent is historically the home of more human pathogens than any other, and the people who lived through the epidemics that wracked Athens and Constantinople said their disease came from there. The epidemic in Constantinople, for instance, seems to have come via trade routes from the Central African interior. “And I’m sure that disease was the same as the Black Death,” says O’Brien.

One way to solve the puzzle could be to look for the pathogen’s DNA in the plague pits of Europe. Didier Raoult and colleagues at the University of the Mediterranean in Marseilles examined three skeletons in a 14th-century mass grave in Montpellier last year (New Scientist, 11 November 2000, p 31). They searched the skeletons for fragments of DNA unique to several known pathogens-Yersinia, anthrax or typhus. They found one match: Yersinia. In their report they wrote: “We believe that we can end the controversy. Medieval Black Death was [bubonic] plague.”

Not so fast, says Scott. Southern France probably had bubonic plague at that time, even if it wasn’t the Black Death. Moreover, attempts by Alan Cooper, director of the Ancient Biomolecules Centre at Oxford University, and Raoult’s team to replicate the results have so far failed, says Cooper. Similar attempts to find Yersinia DNA at mass graves in London, Copenhagen and another burial in southern France have also failed.

It’s too early to conclude that the failure to find Yersinia DNA means the bacterium wasn’t there, though. The art of retrieving ancient DNA is still in its infancy, Cooper warns. Pathogen DNA – -especially that of fragile viruses – -is extremely difficult to reliably identify in remains that are centuries old. “The pathogen decays along with its victim,” he says. Scientists have had difficulty, for example, in retrieving the 1918 flu virus, even from bodies less than a century old and preserved by permafrost. And even if the technique for retrieving ancient DNA improves, you need to know what you’re searching for. There is no way now to search for an unknown haemorrhagic virus.

But the possibility that the Black Death could strike again should give scientists the incentive to keep trying. The similarity of the catastrophes in Athens, Constantinople and medieval Europe suggests that whatever the pathogen is, it comes out of hiding every few centuries. And the last outbreak was its fastest and most murderous. What would it do in the modern world? Maybe we should find it, before it finds us.

‘Spillover’ diseases are emerging faster than ever before—thanks to humans

History is pockmarked with the scars of past zoonotic outbreaks. What have we learned, why are they increasing, and what can we do to avoid them?

(Update 10/9/2021)

When a dozen merchant ships from the Black Sea docked in Messina, Sicily, in October 1347, they carried a deadly cargo that would change the course of history.

Most of the sailors onboard were dead. The few survivors were covered in oozing, black pustules. Though authorities quickly ordered all people to remain onboard the “death ships,” rats had already disembarked. They and the fleas they carried were infected with Yersinia pestis, the bacterium that causes bubonic plague.

Over the next five years, the Black Death swept Europe, killing 34 to 50 million people—between a third and a half of the population at the time. Scholars at the University of Paris blamed the contagion on a dangerous “triple [astrological] conjunction of Saturn, Jupiter and Mars.”

Nearly seven centuries after the Black Plague hit Europe, yet another pandemic is raging. This time scientists know it’s caused by a virus, and modern germ theory coupled with advanced gene sequencing mean we have the tools to study its weaknesses and curb its spread. Nevertheless, the current recorded death toll from COVID-19 has surpassed 4.8 million, and experts say true numbers are far higher.

Deadly outbreaks and novel diseases have challenged human existence throughout history, profoundly impacting economics, culture, and commerce, killing world leaders and bringing down empires, says David Morens, a zoonotic disease expert at the National Institute of Allergy and Infectious Diseases. Many of the viruses and bacteria behind these outbreaks existed for millennia without causing widespread harm. Human behavior has changed that. “Few people realize that measles, plague, and other diseases go back thousands of years, with Neolithic origins,” he says.

The growing human population, increasing globalization, and environmental damage are all accelerating the process, says William Karesh, an executive vice president at EcoHealth Alliance, a New York-based nonprofit that studies zoonoses, or diseases that spread between animals and humans. “The laws of biology haven’t changed, but the playing field has changed dramatically,” he says.

The result: Dangerous new human diseases are emerging at unprecedented rates, including Marburg virus, avian flu, AIDS, severe acute respiratory syndrome (SARS), Nipah virus, swine flu, Ebola, Lyme disease, chikungunya, Zika, dengue, Lassa fever, yellow fever, and now COVID-19. Some 2.5 billion people are infected with zoonotic diseases each year, and because many of these ailments have no cure, they kill about 2.7 million annually, according to the U.S. Centers for Disease Control and Prevention.

Unlike previous centuries when diseases took time to spread, the infected can now board a plane and disseminate their germs worldwide before they even show symptoms. COVID-19 emerged in China just 21 months ago, and cases have since been reported in 223 countries and territories. Humans have also enabled disease-carrying ticks and mosquitoes to expand their ranges by altering the climate. As the planet warms, these insects move into new territory.

Part of the problem is that forgetting the lessons from past disease outbreaks has become a recurring theme in human history, Morens says. “Almost all the experts I know think that this will keep happening again and again because the problem is not the germs. The problem is our behavior, right?”

The Neolithic revolution

From a pathogen’s perspective, the bonanza of vulnerable hosts began 12,000 years ago during the Neolithic Revolution. Small bands of nomads that rarely came in contact with others couldn’t spawn a pandemic. But once hunter-gatherers transitioned to farming and congregated in large, crowded settlements, infectious microbes flourished.

There were many opportunities for infection. Settlers shared the land with wild species. They domesticated wolves as companions, and later, tamed and lived with wild sheep, goats, and cows they used as livestock. Grain stores attracted flea- and tick-infected rodents. Standing water in wells and irrigation systems allowed mosquitoes to flourish.

In close contact, all of them swapped pathogens and parasites, allowing zoonotic diseases to jump the Darwinian divide between animals and humans. Some 60 percent of humankind’s deadliest killers originated in animals, including smallpox, cholera, and influenza. “Some may have jumped multiple times before successfully infecting people,” says Timothy Newfield, a historical epidemiologist at Georgetown University.

Some diseases use “middlemen” as part of their jump between species. Livestock often fill that role, acting as an intermediary host between wildlife and humans. One example is Nipah virus, which jumped from wild fruit bats to domesticated pigs to humans in Malaysia in 1998. Livestock sometimes becomes reservoirs for diseases: for example, people transmitted tuberculosis to cows, some of which now harbor the bacterium that causes it, allowing the disease to keep moving between species.

Still, it’s a roll of the dice what happens once pathogens find a new host, Morens says. Factors such as contagion level, how a disease is spread, and the availability of appropriate hosts dictate whether an emerging disease becomes a dead-end infection, as most do, or explodes into a serious outbreak.

The rise of outbreaks

Historical accounts offer glimpses into ancient pandemics. Mesopotamian cuneiform tablets, the world’s oldest surviving writings, describe plague and pestilence that raged in 2000 B.C. These writings blame angry gods for illnesses, or sometimes, the demons they enlisted, which were known as “the hand of a ghost,” says Troels Pank Arbøll, an Assyrian historian at the University of Oxford. Celestial conjunctions involving the planet Mars, which was linked to the Assyrian god of death, could portend an epidemic.

The cuneiform texts describe how venerated healers diagnosed patients. Male exorcists or physicians combined physical examination with environmental observations, which could be anything from a creaking door in the house to animals that appeared. How those animals moved was indicative of their impact: from the right, propitious, from the left, not good, Troels says.

The healers would then consult written “omens” to concoct and administer herbal remedies, which they applied as poultices or poured into the appropriate orifice. They chanted incantations and prayers to appease the deities and ritually dispelled symptoms by melting a figurine of the patient in a fire or tossing it in a river.

Warnings about rabid dogs are the tablets’ only mention of zoonotic disease. But other ancient evidence exists. Smallpox is described in early Indian, Chinese, and Egyptian writings. When archaeologists discovered the mummy of ancient Egyptian Pharaoh Ramses V in 1898, they found his skin pocked with scars. He, along with two other mummies, revealed that smallpox has existed for at least 3,000 years. Researchers note that it may have jumped from a rodent pox virus; rodents are also a reservoir for closely related cowpox and camelpox.

One of history’s first documented plagues—the virulent Plague of Athens—ravaged ancient Greece from 430 to 425 B.C. As growing settlements and rising cities facilitated infection, people evolved resistance to local diseases. Then they began to travel, unwittingly spreading germs across the ancient world in a process Morens calls “pathogen pollution.”

The Athens plague is thought to have arrived by sea, ravaging a city ripe for contagion. At the time, Athens was embroiled in war with neighboring Sparta and the city was crowded with refugees.

The historian Thucydides lived in Athens during the plague and vividly detailed the symptoms. People’s heads burned with fever, their mouths bled, eyes turned red, they coughed, vomited, had dysentery, and developed an unquenchable thirst. Their reddened skin erupted in ulcers. Most were dead within a week. The suffering “seemed almost beyond the capacity of human nature to endure,” Thucydides wrote in the History of the Peloponnesian War.

Scavenger animals avoided the unburied dead. Enveloped in a specter of death, the city descended into “unprecedented lawlessness … the catastrophe was so overwhelming that men, not knowing what would happen next to them, became indifferent to every rule of religion or of law,” Thucydides wrote.

This mysterious pestilence still has not been identified, though experts suggest it could have been anthrax, smallpox, typhus, or any of two dozen other infectious candidates. Whatever it was, the plague killed tens of thousands, and a weakened Athens fell to Sparta in 404 B.C.

Altering history with waves of disease

Over the next few centuries, devastating waves of bubonic plague, measles, and smallpox annihilated huge numbers of people across three continents.

“It shows how interconnected the world was 2,000 years ago,” says Lucie Laumonier, a historian at Montreal’s Concordia University. The Silk Road and trading ships connected Europe with North Africa and Asia, creating big opportunities for microbes, with each outbreak altering human history in its own way.

A pandemic may have sped the demise of the Han Empire in A.D. 160. Just five years later, Roman armies returning home from Western Asia imported an unknown disease that caused the Plague of Antonius. It killed emperor Marcus Aurelius as well as five million Romans and devastated the empire, impacting both the military and agriculture and emptying state coffers.

The Justinianic Plague struck Constantinople, now Istanbul, during the sixth century, the first of three pandemics of bubonic and pneumonic plague. They rank among humanity’s most fatal biological events, says Georgetown’s Timothy Newfield.

The historian Procopius, who carefully chronicled Emperor Justinian’s reign, wrote that “there was a pestilence, by which the whole human race came near to being annihilated.” He claimed it came from Egypt, which shipped wheat to Constantinople. That’s feasible: Grain shipments back then could have carried plague-bearing rodents and fleas.

Mongol armies may have been responsible for the next bubonic plague pandemic by unwittingly bringing flea-infested rats from Central Asia to Ukraine in 1346 during the siege of Kaffa. Some historians have suggested that the Mongols used biological warfare and catapulted diseased corpses over the city walls to infect those inside—however, evidence is limited, and critics have since called that idea into question.

Either way, the survivors fled, sailing from the Black Sea to Genoa and Messina and bringing the Black Death with them. Within three years the disease had spread to England, Germany, and Russia.

In 1348, Italian poet Giovanni Boccaccio described the bubonic plague as a disease that “would rush upon its victims with the speed of a fire racing through dry or oily substances … Swellings, either on the groin or under the armpits … waxed to the bigness of a common apple, others to the size of an egg.” These buboes turned black and purple, seeping blood and pus. Victims shook with fever, aches, and digestive distress.

To try to cure them, doctors often used bloodletting or induced vomiting. Most of the infected quickly succumbed. “The scale of mortality was unlike anything that we can even imagine,” says Newfield.

Superstition ruled. Some people believed planetary movements, bad air, or poisoned water caused this deadly pestilence. Many thought it was a punishment from God. Other people blamed outsiders. Various minority groups were driven away, tortured, or killed. “The desire to scapegoat is very, very old,” Newfield says.

Meanwhile, rats and fleas thrived in cities without regular garbage collection. They burrowed into rugs made from wetland rushes and nibbled leftovers that were thrown to pet cats and dogs. Their role in the pandemic went unnoticed, along with lice that may also have been carriers.

Back in Asia, the plague killed some 16 million people. Since pandemics limit travel and trade, this plague caused the Mongols to lose control of Persia and China, and that ultimately dissembled their empire.

Ancient roots of prevention

Fear of contagion during this second plague outbreak sparked countermeasures that are still in use today.

In 1377, in the Venetian-controlled port of Ragusa (now Dubrovnik, Croatia), officials set up a place outside the city to treat the town’s sick residents. They also isolated all ships and overland caravans for 30 days before allowing travelers entry to the city. That later stretched to 40 days—or quarantino in Italian. These measures created the cornerstone of Medieval preventative social distancing.

Still, the plague ebbed and recurred for the next 400 years. A ferocious 1664 outbreak in London is famous for ”dead carts” that clattered along cobblestone streets with drivers shouting, ”Bring out your dead,” immortalized by Monty Python. The last of the three bubonic plague pandemics began in the Chinese province of Yunan around 1855 and lasted until 1960.

It was during this episode that Swiss scientist Alexandre Yersin discovered the bacterial cause in 1894. Four years later, Jean-Paul Simond traced transmission from rodents to fleas to humans. When bubonic plague crossed the Pacific and reached San Francisco in 1900, officials rejected the accumulated science, instead quarantining Asian immigrants.

In 1897, scientists developed a preliminary vaccine; a better version emerged in 1931, and antibiotic treatment proved effective in 1947. With these tools in hand, plague in humans can be controlled and large outbreaks are far less likely. However, the bacteria are still circulating in the wild. Plague was in the headlines just this August after it was detected in chipmunks in Lake Tahoe, California, forcing some tourist destinations to shut down.

The modern viral explosion

Various viruses have also haunted humankind, and smallpox was among the deadliest. From the time of ancient Egypt onward, “the speckled monster” infected the Old World, often leaving survivors horribly scarred or blind. It killed 25 to 40 percent of victims, including pharaohs, nobles and royalty: China’s Shunzi Emperor (1661), Queen Mary II of England (1694), Habsburg Emperor Joseph I (1711) , Russia’s Czar Peter II (1730), and Louis XV of France (1774), among others. It’s thought that Japan’s Emperor Komei died of smallpox in 1867. Queen Elizabeth I of England and U.S. President Abraham Lincoln barely survived infection.

By contrast, the New World had been comparatively free of pandemic disease, possibly because indigenous peoples domesticated fewer animal species, offering fewer opportunities for germs to jump to humans. That ended when the conquistadors carried Eurasian germs across the Atlantic. The hueyzahautal—or “great eruption”—of smallpox exploded in Mexico in 1520 and spread into South America, slaying some 3.5 million people, including Aztec emperor Cuitláhuac and Incan emperor Huayna Capac. It crippled both empires and facilitated Spanish conquests.

“The age of exploration might more appropriately be called the age of global microbial devastation,” says Morens.

Notably, an exponential rise in human population that also started around the 1500s brought with it a sharp increase in dangerous epidemics and pandemics.

In 1793 U.S. President George Washington was confronted by the “American plague” of yellow fever, which would burn its way across the country for the next six years. In 1832 a cholera pandemic spread from India into Europe, killing more than 18,000. And the devastating 1918 influenza pandemic erupted near the end of World War I, killing at least 50 million worldwide. From 1900 to today, the world has been introduced to microbial killers ranging from HIV, the H1N1 swine flu, Zika virus, and infectious coronaviruses that are still wreaking havoc.

Still, there is no global pandemic prevention strategy. Morens notes that since COVID-19 emerged in late 2019, there has been growing discussion of the need for greater surveillance, international communication, and vaccine development. But there has been little mention of mitigating the human activities that boost the risk of dangerous disease, he says. That includes deforesting land, encroaching into wild ecosystems and selling and consuming wild animals, actions that bring wildlife, livestock, and humans into close contact.

Global cooperation in a unified “one health” effort is needed to prevent the next pandemic, says Steve Osofsky, director of the Cornell Wildlife Health Center in Ithaca, New York. It’s an approach that “recognizes the relationships between our own health, the health of our domestic animals, and the health of wildlife and how all that’s underpinned by environmental stewardship,” he says. This framework will protect both humanity and nature, but, he adds, it requires collaborations between a wide spectrum of experts, from medical doctors, veterinarians, epidemiologists, zoologists, business leaders and Indigenous peoples to agriculture, public health, and environment professionals. “How we treat the natural world has direct bearing on our future,” Osofsky says.

‘Historic moment’: Why the WHO endorsed the first malaria vaccine

The move marks the start of a highly anticipated rollout for this type of vaccine, which experts say could boost the health of millions of at-risk children.

(Update 10/9/2021)

For millions of people, malaria creates a grim drumbeat of death, heartbreak, and loss: Every seven seconds, someone gets a case of malaria, and every two minutes, the disease claims another victim under the age of five. That’s why public health experts rejoiced yesterday when the World Health Organization made a landmark decision to endorse the first vaccine against malaria.

Years of clinical trials have shown that this vaccine—known as RTS,S/AS01, or Mosquirix—is safe and helps protect against the disease, especially in concert with other malaria-fighting tools. With a 12-month efficacy of 56 percent, RTS,S lacks the eye-popping effectiveness of other modern vaccines. However, the vaccine’s target—the parasite Plasmodium falciparum—is orders of magnitude more complex than a virus.

“We have a number of things in our toolkit to fight malaria, and they’re all used together: bed nets, spraying, chemoprevention,” says Sean Murphy, a malaria vaccine developer at the University of Washington in Seattle. “This vaccine cannot replace all those tools.”

Also, the WHO recommendation doesn’t immediately usher in widespread use of RTS,S. Rather, it marks the beginning of the vaccine’s broader rollout and paves the way for individual African countries to issue their own approvals of the vaccine, with WHO assistance. Scaling up to the necessary tens of millions of annual doses will require billions of dollars of government and philanthropic donations to the international nonprofit GAVI, the Vaccine Alliance, which coordinates the financing of vaccination programs in developing countries.

But assuming the rollout begins soon, the benefits of this vaccine could be transformative at scale. In a study published last November in PLoS Medicine, researchers found that if 30 million doses of RTS,S were efficiently administered each year across subregions of 21 African countries, the vaccine could avert between 2.8 million and 6.8 million malaria cases each year—and save the lives of between 11,000 and 35,000 children under the age of five.

“I longed for the day that we would have an effective vaccine against this ancient and terrible disease,” Tedros Adhanom Ghebreyesus, the WHO’s director-general, said in a Wednesday press briefing. “Today is that day, a historic day.”

Designing the vaccine

In the past two decades, the world has made enormous progress toward curbing malaria thanks to widespread use of bed nets, rapid diagnosis, and the seasonal use of preventive antimalarial drugs. Between 2000 and 2015, with all of these interventions, the incidence of malaria cases among at-risk populations fell by 27 percent. But recently, progress has stalled. Between 2015 and 2020, cases declined by less than 2 percent.

In 2019, the world saw an estimated 229 million cases of malaria, 94 percent of which occurred in Africa. Millions of cases of malaria also occurred across Asia, the Middle East, and the Americas. In sum, these cases resulted in the deaths of some 409,000 people, two-thirds of whom were young children.

To drive meaningful progress against malaria once again, the WHO has been eager to introduce a malaria vaccine into the mix. More than 140 different malaria vaccine candidates are in development. Until RTS,S, none had won the WHO’s formal endorsement.

Making a malaria vaccine is extremely tricky because of the disease’s complexity. Most cases of malaria are caused by the parasite Plasmodium falciparum, whose genome contains more than 5,000 genes, far more than the mere 12 genes rattling around inside SARS-CoV-2, the coronavirus behind COVID-19. Further complicating matters, Plasmodium goes through multiple life stages as infections spread from the bloodstream into the liver and then back into the bloodstream, when the parasite infects red blood cells themselves.

“Viruses, certainly are very complex … [but] when you’re doing vaccine development, it’s very straightforward,” says Jason Kindrachuk, a virologist at the University of Manitoba in Winnipeg. With parasites, however, “we’re talking about organisms that are responsive to their surroundings and can change and adapt.”

“Why didn’t we have a vaccine sooner? It’s certainly not for a lack of trying,” he adds.

For decades, researchers have focused on the spore-like stage of Plasmodium—called a sporozoite—that first enters the human bloodstream and eventually wends its way to the liver. In 1983, researchers found that sporozoites are covered in a protein, called CSP, that provokes a strong immune response. In 1987, researchers at the U.S. pharmaceutical company GlaxoSmithKline and the U.S.’s Walter Reed Army Institute of Research decided to make a vaccine based on this protein.

The researchers’ idea was to engineer carrier proteins—in this case, a surface protein from the hepatitis B virus—that were studded with bits of CSP. These proteins would then self-assemble into microscopic blobs called “virus-like particles” that would trigger the immune system to make antibodies against CSP. That way, any Plasmodium sporozoites slathered in CSP would provoke an immediate immune response. (If you’ve been vaccinated for human papillomavirus (HPV) or hepatitis B, you’ve already received a vaccine based on a virus-like particle that’s customized to that particular pathogen.)

After a promising human “challenge” trial in 1996, researchers spent two decades building out clinical trials in African countries, publishing the key phase three trial results in 2015. The main reason for the lengthy process: safety. The target population for RTS,S is young children ages five to 18 months, but to prove the vaccine’s safety and efficacy, researchers had to start with adult clinical trials and work their way down to younger age groups.

“Some criticized the pace with which we did that, but we felt that, really, the safety of those kids and their vulnerability was such that we needed to proceed very, very carefully,” says Joe Cohen, who co-invented RTS,S while a researcher at GlaxoSmithKline.

Since 2019 more than 800,000 children in Ghana, Kenya, and Malawi have received at least one dose of the vaccine through a WHO pilot program. So far, the program has reported a 30-percent decrease in severe malaria cases among vaccinated children, on top of declines realized from other interventions such as bed nets.

Now Cohen is overjoyed to hear the WHO’s endorsement of the vaccine he helped guide through those decades of studies and trials. “I don’t know how to find the right words,” he says. “What a relief, and what an extraordinary thrill to know that the vaccine soon can be deployed widely and have a tremendous impact on public health in Africa.”

Layers of protection

Relative to the astoundingly effective COVID-19 vaccines and other routine vaccines, RTS,S may look like a modest performer. Phase three trials found that the shot had 56 percent efficacy among children between five and 17 months old in the first year after vaccination. When evaluated over four years, the vaccine’s efficacy dropped to roughly 36 percent.

WHO epidemiologist Mary Hamel, who manages the organization’s Malaria Vaccine Implementation Program, emphasized in a May interview that RTS,S does enough to make a difference in the fight against malaria. “To put this in perspective, [RTS,S has] about the same efficacy as the efficacy of a bed net, and we’ve seen the dramatic decline in malaria morbidity and mortality with bed nets,” she said. “This is something you could add on top.”

That additive benefit could be substantial. In a study published last month in the New England Journal of Medicine, researchers led by Daniel Chandramohan of the London School of Hygiene and Tropical Medicine found that combining RTS,S and preventive antimalarial drugs could reduce children’s risk of severe malaria by 70 percent.

The WHO pilot program has also found that more than two-thirds of children in Ghana, Kenya, and Malawi who are not sleeping under a bednet are benefiting from the RTS,S vaccine. If given alongside other childhood vaccinations, large numbers of children who currently can’t access other malaria interventions would at least have the protection of RTS,S.

When considering malaria’s lifelong effects on children’s physical and cognitive development, the vaccine’s benefits accrue all the more, adds Alejandro Cravioto, the chair of the WHO’s Strategic Advisory Group of Experts on Immunization. “A child that is repetitively sick is maimed for life,” Cravioto said in the Wednesday briefing. “In that sense, having anything that protects them, or helps them to be less sick during this growth phase, is essential.”

Rolling out the vaccine

Kate O’Brien, director of the WHO’s department of immunization, vaccines, and biologicals, said in the Wednesday briefing that GAVI will deliberate in early December over how much to invest in RTS,S. So far, GAVI and partner organizations have committed nearly $70 million to the WHO pilot program of RTS,S, which has administered 2.3 million doses so far.

In a statement, GlaxoSmithKline committed to supplying up to 15 million doses of RTS,S each year if funding and recommendations for the vaccine’s wider use fell into place. The company is also working to transfer production of the vaccine to the Indian company Bharat Biotech, which the Wall Street Journal reports would happen by 2028. GlaxoSmithKline also committed to selling the vaccines at no more than 5 percent higher than the cost of production.

Also on the table for discussion are dosing regimens. While the WHO pilot project has gone fairly smoothly so far, especially considering the added challenges of COVID-19, the vaccine is currently given in a four-dose regimen: three shots in three months, beginning at five months of age, and then a fourth booster shot at roughly 18 months old. In the WHO briefing, O’Brien added that the fourth booster’s necessity is still being evaluated.

In the long term RTS,S almost certainly won’t be the last malaria vaccine to win the WHO’s formal recommendation. The WHO has recognized that vaccines with even higher efficacies than RTS,S would save additional lives, so it set an audacious goal in 2013. By 2030, the health agency proclaimed, it wanted to see a 75-percent effective malaria vaccine.

A next-generation update to RTS,S, called R21, may be the first to claim that title. Lab studies of R21 began at Oxford from 2010 to 2012, and in 2019, researchers had worked up to a 450-person phase two trial in Burkina Faso’s Nanoro health district—which found that R21 had a remarkable 77-percent efficacy. Other vaccines are in development, including some based on harmless “attenuated” Plasmodium parasites that are administered via IV.

Though many steps remain in rolling out RTS,S and other malaria vaccines, world health officials are keeping their gazes on one thing above all else: a bright glimmer of hope.

“We still have a very long road to travel, but this is a long stride down that road,” Ghebreyesus said. “This vaccine is a gift to the world.”

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