Smallpox

Based on Wikipedia: Smallpox

In 1980, humanity did something it had never done before and has only managed once since: we drove a disease to extinction. Smallpox, a virus that killed an estimated 300 million people in the twentieth century alone—more than both World Wars combined—simply ceased to exist in the wild. The last person to catch it naturally was a hospital cook in Somalia in October 1977. Three years later, the World Health Organization made it official. Smallpox was gone.

This is the story of the deadliest infectious disease in human history, and how we finally beat it.

The Speckled Monster

The English called it the "speckled monster." They also called it simply "the pox"—which tells you something about how common it was. The word "smallpox" itself only emerged in the sixteenth century, when doctors needed to distinguish it from "the great pox," their term for syphilis. Other cultures called it the red plague. Whatever the name, people everywhere knew what it looked like and what it meant.

The disease began deceptively. A fever, some muscle pain, headache, fatigue—nothing that would immediately distinguish it from the flu. Then came the vomiting. Then, after two to four days of this prodromal phase (the medical term for the early warning symptoms before the main event), something changed. Small reddish spots appeared inside the mouth, on the tongue, along the palate and throat. The fever would actually drop at this point, briefly offering false hope.

But the virus was just getting started.

Within one to two days after those mouth sores appeared, a rash erupted on the skin. It followed a distinctive pattern that helped doctors diagnose it: starting on the forehead, spreading rapidly across the face, then moving outward to the arms and legs, and finally reaching the trunk. Within 36 hours, the progression was complete. The rash was most concentrated on the face and the extremities—the palms and soles were almost always involved—while the trunk was relatively spared. This "centrifugal" distribution, denser at the edges than the center, was the opposite of chickenpox, which clusters on the torso.

Then the real horror began.

The spots became raised bumps. The bumps filled with a clear fluid, becoming vesicles. The fluid turned cloudy and opaque, and the vesicles became pustules—tense, firm, round blisters embedded deep in the skin. Doctors described them as feeling like small beads under the surface. By the sixth or seventh day of the rash, every lesion had become a pustule.

Between the seventh and tenth days, the pustules reached their maximum size. Then they slowly began to deflate and dry out, forming scabs. By the end of the second week, the scabs started falling off. Where they fell, they left depigmented scars—the distinctive pockmarks that gave survivors their telltale appearance for life.

The overall death rate was around 30 percent. But survival didn't mean escape. Many survivors were left blind, their eyes destroyed by the virus. Others bore such extensive scarring that they were disfigured beyond recognition.

The Varieties of Horror

Not all smallpox was created equal. Scientists eventually identified two distinct strains of the virus. Variola major was the severe form, the one that killed 30 percent of those it infected. Variola minor, sometimes called alastrim, was its gentler cousin, with death rates of one percent or less. The two were different enough that infection with one didn't necessarily protect you from the other.

But even within variola major, the disease could manifest in startlingly different ways. Doctors eventually classified four types based on how the rash developed.

The ordinary type accounted for about 90 percent of cases in unvaccinated people. This was the "classic" progression: papules to vesicles to pustules to scabs. Even this most common form came in two flavors. In discrete smallpox, the pustules remained separate from each other, standing out individually on the skin. In confluent smallpox, the blisters merged together into sheets, sometimes causing the outer layers of skin to separate from the underlying flesh. Confluent cases had a 62 percent death rate.

Modified smallpox occurred mainly in people who had been previously vaccinated. The disease was milder, the lesions fewer and more superficial, evolving faster and leaving less damage. It was almost never fatal. This is what vaccination was supposed to do: not necessarily prevent infection entirely, but render it survivable.

Then there were the nightmare variants.

Malignant smallpox, also called flat smallpox, made up about five to ten percent of cases, most of them in children. The lesions never rose properly from the skin. Instead of becoming tense, raised pustules, they stayed almost flush with the surface, soft and velvety to the touch. The prodromal phase was more severe and prolonged, and the rash on the mucous membranes was extensive. Most people with this form died between the eighth and twelfth day. Scientists believe it resulted from a defective immune response—the body simply couldn't mount the cellular defenses needed to fight the virus properly. In the rare cases where patients survived, the lesions simply faded away without forming the typical scabs or scars.

The most terrifying form was hemorrhagic smallpox. In about two percent of infections, mostly in adults, something went catastrophically wrong with blood clotting. Bleeding occurred everywhere: into the skin, the mucous membranes, the gastrointestinal tract, the internal organs. The skin turned dusky, then began to look charred and black. Physicians called this variola nigra—black pox.

There were two sub-types of hemorrhagic smallpox, and both were almost universally fatal.

The early form, called purpura variolosa, began with severe headache, high fever, and abdominal pain. Within days, the skin flushed red, then petechiae appeared—tiny spots of bleeding under the skin—followed by larger hemorrhages. Most patients died suddenly between the fifth and seventh day, often when only a few visible skin lesions had even appeared. They typically remained conscious until death or shortly before. Autopsy revealed bleeding throughout the body: in the spleen, kidneys, liver, heart, muscles, bladder. The diagnosis was frequently missed until after death.

Pregnant women were especially vulnerable. About 16 percent of unvaccinated pregnant women with smallpox developed early hemorrhagic disease, compared to roughly one percent of other adults. The case fatality rate approached 100 percent.

The late hemorrhagic form developed somewhat differently. The rash appeared but often failed to progress beyond the vesicular stage. Bleeding occurred within and around the lesions. Sometimes pustules formed but bled at their base. The underlying problem was a collapse of the body's clotting system—all the coagulation factors decreased while substances that prevent clotting increased. About 90 to 95 percent of these patients died within eight to ten days.

Here's a particularly cruel detail: vaccination didn't prevent hemorrhagic smallpox. Some cases occurred in people who had been revaccinated just before becoming infected. Whatever went wrong in these cases, the immune response that protected against ordinary smallpox offered no defense.

A Virus Unlike Any Other

The Variola virus belongs to a family called Poxviridae, in a genus called Orthopoxvirus. Four members of this genus can infect humans: variola (smallpox), vaccinia (used in vaccines), cowpox, and monkeypox. But variola is unique among them. In nature, it infects only humans. The others can jump between humans and various animals, but smallpox had no animal reservoir. This would prove crucial to its eradication.

Poxviruses are giants of the viral world. The Variola particle measures about 302 to 350 nanometers by 244 to 270 nanometers—large enough that early microscopists could actually see them, though they didn't know what they were looking at. For comparison, the influenza virus is about 80 to 120 nanometers across. The COVID-19 coronavirus measures around 120 nanometers in diameter. Smallpox is roughly three times larger.

The virus is brick-shaped, which is unusual. Most viruses are spherical or helical. Its genome is a single linear strand of double-stranded DNA, about 186,000 base pairs long, with distinctive hairpin loops at each end. This is a large genome for a virus—coronaviruses have about 30,000 base pairs, and HIV has only about 9,700.

Poxviruses do something no other human DNA virus does: they replicate in the cytoplasm of the cell rather than in the nucleus. Most DNA viruses need to hijack the host cell's nuclear machinery to copy themselves. Poxviruses carry their own copying equipment, encoded in that unusually large genome. They're essentially self-contained replication factories.

The origins of this virus remain somewhat mysterious. Genetic analysis suggests it evolved from a rodent virus in Africa somewhere between 68,000 and 16,000 years ago—a wide range that reflects uncertainty in how quickly the virus mutates over time. The different estimates come from different methods of calibrating the "molecular clock" that scientists use to date evolutionary divergences.

A related virus called Taterapox still infects African rodents, including gerbils. The best estimate places the split between Taterapox and Variola at about 3,000 to 4,000 years ago. This matches archaeological evidence suggesting smallpox is a relatively recent human disease—though "recent" in evolutionary terms still means millennia.

The earliest physical evidence of smallpox comes from Egyptian mummies dating to around 1500 BCE, including the mummy of Pharaoh Ramses V, who died in 1145 BCE and whose face bears what appear to be pockmark scars. If the genetic dating is correct, the virus had already been circulating in human populations for at least a thousand years by then, gradually adapting to its new host.

Conquest by Contagion

Smallpox spread in a distinctive way. Unlike measles or influenza, which can travel on tiny airborne droplets across considerable distances, smallpox required prolonged face-to-face contact. The virus shed primarily through the respiratory tract during that brief window when mouth sores erupted and released enormous quantities of viral particles into the saliva. It could also spread through contact with contaminated bedding or clothing, though this was rarer.

This transmission pattern meant smallpox moved relatively slowly through populations. It needed sustained close contact—the kind that happens within households, in crowded living conditions, among caregivers and their patients. In communities that had never encountered it before, the virus would smolder for a while, then explode.

The consequences for populations without prior exposure were catastrophic. When European explorers and colonizers reached the Americas, they carried smallpox with them. The indigenous peoples of the New World had no immunity whatsoever. The virus moved faster than the explorers themselves, spreading along trade routes and through population movements, reaching some communities before any European had ever set foot there.

The numbers are difficult to calculate precisely, but the demographic collapse was staggering. Some historians estimate that 90 percent of the pre-Columbian population of the Americas died within a century of contact, with smallpox bearing much of the blame alongside measles, typhus, and other Old World diseases. Entire civilizations collapsed. The Aztec and Incan empires, already under military assault by Spanish conquistadors, found their populations decimated by invisible enemies far more deadly than any soldier.

This wasn't unique to the Americas. Wherever smallpox reached immunologically naive populations—Australia, Pacific island chains, isolated communities—it wreaked similar devastation. The pattern repeated itself over centuries.

In populations where smallpox had been endemic for generations, the situation was different but hardly better. By the eighteenth century in Europe, the disease had become a childhood affliction. Most people either caught it young and survived (gaining immunity) or died from it. An estimated 400,000 Europeans died from smallpox every year during that century. One-third of all blindness was attributed to the disease. The survivors—the pockmarked faces, the empty eye sockets—were everywhere.

Royalty offered no protection. Smallpox killed six European monarchs during the eighteenth century alone, including Louis XV of France, who died from it in 1774. Queen Mary II of England had died from it in 1694. The Habsburg emperor Joseph I succumbed in 1711. The Romanov tsar Peter II died of it in 1730. Crowns and castles couldn't stop a virus.

The First Vaccine

Long before modern medicine understood what viruses were or how the immune system worked, people noticed something important: if you survived smallpox once, you didn't get it again. This observation led to a practice called inoculation or variolation—deliberately infecting people with material from smallpox lesions, hoping to induce a mild case that would confer lifelong immunity.

The practice appears to have originated in China around the 1500s. Chinese physicians ground up smallpox scabs into powder and had patients inhale it. Alternatively, they might take fluid from a pustule and introduce it through a scratch in the skin. The idea spread along trade routes to India, the Ottoman Empire, and eventually Europe.

Lady Mary Wortley Montagu, wife of the British ambassador to the Ottoman Empire, encountered variolation in Constantinople in 1717. She had survived smallpox herself in 1715 but was left badly scarred; her brother had died from the disease. Impressed by the Ottoman practice, she had her son inoculated in 1718 and championed the technique upon her return to England.

Variolation worked, but it was dangerous. The induced infection was usually milder than naturally acquired smallpox, but not always. About two to three percent of those inoculated died—far better than the 30 percent mortality of natural infection, but still a significant risk. And inoculated patients were fully contagious, potentially spreading the disease to others.

Then came Edward Jenner.

Jenner was a country doctor in Gloucestershire, England. He had heard the folk belief among milkmaids that those who caught cowpox—a mild disease transmitted from infected cow udders—never got smallpox. The claim had circulated for decades, but no one had systematically tested it.

In 1796, Jenner conducted his famous experiment. He took material from a cowpox lesion on the hand of a milkmaid named Sarah Nelmes and inoculated it into a young boy named James Phipps. The boy developed a mild cowpox infection. Six weeks later, Jenner inoculated him with actual smallpox material. The boy didn't develop the disease.

Jenner called his technique "vaccination," from vacca, the Latin word for cow. The term would eventually be generalized to mean any immunization procedure, but it began specifically with cowpox.

The genius of vaccination over variolation was safety. Cowpox didn't kill people. It didn't spread from person to person. Yet somehow, infection with this mild animal virus taught the human immune system to recognize and fight its deadly cousin. We now understand that the two viruses are similar enough that antibodies against cowpox cross-react with smallpox, but different enough that cowpox poses no serious threat to humans.

Vaccination spread across Europe and then the world with remarkable speed. By the early 1800s, it was being practiced on every inhabited continent. Governments began organizing vaccination campaigns. The Spanish launched an expedition in 1803 to carry the vaccine to their colonies in the Americas and Asia, using a chain of orphan boys who were vaccinated one after another to keep the virus alive during the long sea voyages.

But global eradication remained far away. Vaccination was spotty, irregular, and didn't reach everyone. The vaccine itself was difficult to produce and transport—it required fresh material from cowpox lesions or, later, from the vaccinia virus grown on calf skin. Refrigeration didn't exist for most of this period. And while vaccination could prevent smallpox, it couldn't eliminate it from populations where the disease was already endemic.

The Eradication Campaign

The twentieth century brought both the worst of smallpox and its final defeat.

The disease killed an estimated 300 million people between 1900 and 1977. Even in 1967, when the World Health Organization launched its Intensified Smallpox Eradication Programme, there were still an estimated 15 million cases per year worldwide, causing two million deaths. The virus remained endemic across large swaths of Africa, Asia, and South America.

But eradication was now conceivable. The tools existed: an effective vaccine, a disease that spread slowly enough to be tracked, and—crucially—no animal reservoir. Unlike yellow fever (which lives in mosquitoes and monkeys) or plague (which lives in rodents and their fleas), smallpox existed only in humans. Eliminate human cases, and the virus would have nowhere to go.

The campaign that followed is one of the great public health achievements in human history.

It required extraordinary coordination across Cold War boundaries. Soviet scientists worked alongside Americans. WHO teams penetrated war zones, crossed closed borders, navigated corrupt bureaucracies, and overcame cultural resistance. They developed new techniques, including bifurcated needles that made vaccination faster and easier, and jet injectors that could vaccinate thousands of people per day.

Perhaps most importantly, they shifted strategy. Early eradication efforts focused on mass vaccination—trying to immunize entire populations. This proved impractical in many settings. Instead, the WHO adopted "ring vaccination" or "surveillance and containment." When a case of smallpox was identified, teams would rush to vaccinate everyone who had contact with the patient, and everyone who had contact with those contacts, creating a ring of immunity around each outbreak.

This approach exploited smallpox's distinctive epidemiology. The disease's long incubation period—seven to fourteen days between infection and first symptoms—gave vaccinators time to act. And because the virus spread slowly, through prolonged contact rather than casual exposure, the rings didn't need to be impossibly large.

Country after country eliminated the disease. Brazil declared victory in 1971. Indonesia followed in 1972. The last case in Bangladesh occurred in 1975. India—where the disease had been endemic for millennia—recorded its final case in May 1975.

The virus made its last stand in the Horn of Africa. Ethiopia and Somalia, torn by war and drought, posed enormous logistical challenges. The final natural case occurred in Merca, Somalia, on October 26, 1977. A hospital cook named Ali Maow Maalin developed the rash. He survived.

The World Health Organization waited three years, watching for any resurgence, before officially declaring smallpox eradicated on May 8, 1980.

The Last Death

Except it wasn't quite over.

In September 1978, nearly a year after the last natural case, a medical photographer named Janet Parker developed smallpox in Birmingham, England. She worked at the University of Birmingham Medical School, one floor above a laboratory that was still researching the virus. Somehow—the exact route was never definitively established—the virus had escaped the lab and infected her.

Janet Parker died on September 11, 1978. She was the last person ever killed by smallpox.

The head of the laboratory, Professor Henry Bedson, committed suicide shortly after Parker's diagnosis, before her death. The incident led to worldwide tightening of regulations governing dangerous pathogens and contributed to decisions about what to do with the remaining stocks of variola virus.

The Virus That Won't Die

When smallpox was declared eradicated, laboratories around the world still held samples of the virus. A consolidation process began, eventually concentrating all known stocks in just two facilities: the Centers for Disease Control and Prevention in Atlanta, Georgia, and the Research Institute for Viral Preparations (later VECTOR) in Novosibirsk, Russia.

The question of what to do with these samples has sparked decades of debate.

One view holds that the remaining stocks should be destroyed. The virus is too dangerous to keep around. Laboratory accidents can happen—Janet Parker proved that. The benefits of research cannot justify the risks. No other pathogen of comparable lethality is deliberately preserved. We should finish what the eradication campaign started.

The opposing view argues for retention. Research on the live virus could help develop better vaccines and antiviral treatments. We might need those tools someday—what if smallpox were used as a biological weapon? What if the virus exists in undiscovered locations, frozen in permafrost or hidden in forgotten laboratory freezers? Better to maintain some scientific capability against a pathogen that killed hundreds of millions.

There are also concerns that destroying the official stocks would accomplish nothing if illicit stocks exist elsewhere. Intelligence agencies have long worried that the Soviet biological weapons program, which worked extensively with smallpox, may have left samples in unknown locations. The collapse of the Soviet Union created opportunities for scientists and materials to disperse.

The WHO has repeatedly set deadlines for destruction of the remaining stocks, and those deadlines have repeatedly been extended. As of now, the virus remains in those two freezers in Atlanta and Novosibirsk, guarded but not destroyed.

What Smallpox Teaches Us

The eradication of smallpox demonstrates what humanity can accomplish when it decides that a disease must end. It required international cooperation at the height of the Cold War, sustained funding over many years, and the efforts of thousands of people who tracked down cases in some of the most remote and dangerous places on Earth.

It also required something more fundamental: a disease that was vulnerable to the tools available. Smallpox had no animal reservoir. It spread slowly enough to be contained. The vaccine was highly effective and relatively easy to administer. These characteristics made eradication possible in a way that it isn't for most infectious diseases.

Since 1980, only one other disease has been eradicated: rinderpest, a devastating illness of cattle and other even-toed ungulates, which was declared eliminated in 2011. Polio is close—cases have dropped from hundreds of thousands per year to mere dozens—but the virus persists in a few countries. Guinea worm disease may be next. But for most infectious diseases, eradication remains a distant dream or an impossibility.

The story of smallpox also carries darker lessons. The virus was sometimes weaponized. British forces during the French and Indian War famously gave smallpox-contaminated blankets to Native Americans. The Soviet biological weapons program grew enormous quantities of the virus and worked on making it more lethal. The possibility that smallpox could return as a weapon of mass destruction, deployed by a state or terrorist group, continues to shape policy debates about the remaining laboratory stocks.

For most of human history, smallpox was simply a fact of life—and death. It killed the powerful and the powerless alike. It shaped the fates of continents. It left its mark on survivors in the most literal way possible.

And then we decided it wouldn't exist anymore. We tracked it down, cornered it, and drove it out of the human population. The speckled monster still exists in a few freezers, watched over by scientists and guarded by soldiers. But it no longer hunts us.

In an era when vaccine hesitancy threatens to undo the progress against other diseases, when conspiracy theories spread faster than viruses, when international cooperation feels increasingly fragile, the eradication of smallpox stands as proof of what's possible. We did it once. The question is whether we can summon that same determination again—and whether we can prevent old threats from returning.