Smallpox: The Variola Virus Explained

Smallpox is gone, and that sentence describes something that has happened exactly once. No other human infectious disease has been driven out of existence by deliberate effort. The variola virus, which caused smallpox, killed about 3 in 10 of the people it infected, scarred many survivors for life, and blinded some. On May 8, 1980, the World Health Assembly declared the world free of it. This article explains how the virus worked, why it was so lethal, how it was beaten, and why two freezers still matter.

Educational content, not medical advice. Talk to your doctor before changing any medication, treatment, or routine. Information here reflects current research but every person's situation differs.

Understanding variola is useful beyond the history. The campaign that ended it set the template for modern outbreak response, and the closest living relatives of the virus, including the one that causes mpox, are still circulating in people.

What kind of virus is variola?

Variola belongs to the genus Orthopoxvirus in the family Poxviridae. It is one of the largest viruses that infects humans. Its genome is a single molecule of double-stranded DNA of about 186,000 base pairs, carrying roughly 200 genes (Wikipedia: Variola virus). Many familiar respiratory viruses carry far smaller genomes and far fewer genes, which is part of why poxviruses can afford to be so self-sufficient.

The particle itself is brick-shaped and measures roughly 300 by 250 nanometers. That is large enough that a good light microscope can just pick it out, which is unusual for a virus. Think of most viruses as pocket-sized flash drives and a poxvirus as a full desktop tower: it carries much of the equipment it needs rather than borrowing it.

That equipment matters because poxviruses behave differently from most DNA viruses. They replicate in the cytoplasm of the host cell, not in the nucleus, and they bring their own enzymes for copying DNA and making messenger RNA. The cell supplies raw materials and ribosomes, and little else. For a deeper look at how viruses in general take over a cell, see How Viruses Work: From Infection to Replication.

Variola has one more trait that decided its fate: in nature it infects only humans. Primates and other animals have been infected in laboratory experiments, but the virus had no wild reservoir (a population of animals in which a pathogen persists and can re-enter people). Every case came from another case.

Relatives that share its antigens

The genus also includes cowpox, vaccinia (the virus used in the smallpox vaccine), and monkeypox, now formally called mpox. Their surface proteins are similar enough that an immune response to one partly protects against the others. This overlap is the reason a milder virus could be used to defend against a deadly one. For the closest surviving relative, see our explainer on mpox and the monkeypox virus.

Two strains and four clinical pictures

Two forms of the virus circulated historically. Variola major was the severe one, with a mortality of about 30% in unvaccinated people. Variola minor, also called alastrim, was much milder, with a historical fatality of 1% or less. Infection with either strain gave immunity to the other (Wikipedia: Variola virus).

Variola major itself did not look the same in every patient. Clinicians described four main presentations, and the differences explain why the overall fatality figure hides a wide range.

Clinical type	Who got it	Course and outcome
Ordinary	At least 90% of cases in unvaccinated people	Fatality about 30%; confluent rashes (lesions merging into sheets) carried higher risk, about 62% in one case series
Modified	Mostly people with prior vaccination	Milder rash; rarely, if ever, fatal
Flat (malignant)	Historically 5 to 10% of cases	Lesions never rose into firm pustules; nearly always fatal, usually between days 8 and 12
Hemorrhagic	About 2% of infections, mostly adults	Bleeding into skin and organs; early forms approached 100% fatality, late forms about 90 to 95%

Source: Wikipedia, "Smallpox," summarizing clinical case series; fatality for ordinary smallpox about 30% is also stated by WHO and the CDC.

The modified type is worth noticing. It shows that vaccination did more than prevent infection outright. Even when it failed to stop the virus, it often softened the disease, which is the same pattern seen with many modern vaccines.

How smallpox moved through the body

Variola spread mainly through direct, fairly prolonged face-to-face contact, with respiratory droplets from coughing and sneezing carrying the virus between people (CDC). WHO adds that it spread more slowly than measles or chickenpox, mostly to household members and friends, rather than between strangers passing in the street (WHO). That slower pace turned out to be a strategic gift to the eradication teams.

After exposure there was a silent incubation period. WHO gives 7 to 17 days; most descriptions put the typical window at 7 to 14 days from exposure to the first obvious symptoms. In this phase the person felt well and was not yet contagious.

The timeline of an ordinary case

The illness then followed a recognizable sequence. The table below summarizes the usual course in ordinary smallpox.

Phase	Approximate timing	What happens
Incubation	7 to 14 days	No symptoms; virus multiplies in the body
Prodrome	2 to 4 days	Sudden high fever, headache, backache, exhaustion
Early rash	Following the prodrome	Flat red spots (macules) appear, then become raised papules by about day 2 of the rash
Vesicles	About days 3 to 4	Papules fill with clear fluid
Pustules	About days 6 to 7	Fluid turns to pus; lesions reach full size by days 7 to 10
Scabs	About days 16 to 20	Crusts form and fall off, leaving pitted scars

Source: Wikipedia, "Smallpox," clinical course section.

A person was not notably infectious during the prodrome. Infectivity peaked in the first week of the rash and faded as scabs formed, though a patient was considered contagious until the last scab fell away. Scabs, bedding, and clothing could still carry virus, so nursing staff and family were at risk even after the patient started to recover.

Why the rash gave the disease away

Smallpox had a bedside signature that field workers learned to read. Its lesions advanced together, so on any given day the pustules across the body were nearly uniform in size and stage. Chickenpox arrives in successive crops, so a patient shows spots at several stages at once. Smallpox also tended to cover the palms and soles, where chickenpox usually does not (Wikipedia: Smallpox).

Picture a field of wheat planted in one week versus a garden where seeds went in over a month. In smallpox every lesion is the same age and ripens on the same schedule. In chickenpox you see seedlings, flowers, and fruit at the same time. This visual difference mattered enormously when the job was to find every case in a country with few doctors.

Why it killed

The virus did not simply destroy tissue. Poxviruses carry genes that interfere with the host's immune alarm system, blocking signaling molecules and slowing the response that would normally clear an infection. In severe forms, the combination of massive viral replication and an overwhelmed immune response damaged blood vessels and organs. The hemorrhagic and flat forms, with their near-certain fatality, probably reflect the worst of this mismatch. Researchers still debate why a small share of patients developed these forms, and the question has no settled answer.

What survivors were left with

Most patients recovered, but recovery was not a return to normal. The CDC notes that many survivors had permanent scarring, especially on the face, and that some were left blind (CDC). The scars came from the pustules: when lesions in the deeper layers of skin healed, they left the pitted marks that doctors used to recognize survivors years later.

That visible history had a practical side. A pitted face told anyone who saw it that the person had survived, and survivors did not catch the disease twice, so the scars worked as a public record of who had already been through an epidemic.

Why a virus this large is hard to treat

Because poxviruses make many of their own proteins, they offer drug developers more targets than a small virus does, but they also carry genes that quietly disable parts of the host's defenses. Two broad families of tricks are well documented in the poxvirus literature: proteins that mimic or intercept the host's own signaling molecules, and proteins that block infected cells from sounding an alarm. The practical result was an infection that could slip past early detection long enough to establish itself, which fits with the silent incubation period seen in patients.

Poxviruses also produce two forms of virus particle. One stays inside the cell until it bursts out, and the other leaves wrapped in an extra membrane and spreads to neighboring cells, which helps it travel inside a single body. Several modern antivirals aim at that second, wrapped form, as discussed below.

Thousands of years of a human scourge

Evidence for smallpox is old. Rashes on Egyptian mummies suggest the disease is at least 3,000 years old, and WHO places the earliest evidence around 1350 BCE. The earliest written description appeared in China in the 4th century CE, followed by accounts in India in the 7th century and Asia Minor in the 10th (CDC: Smallpox history).

By the 18th century the burden was immense. A widely cited estimate puts deaths in Europe at about 400,000 a year in that period, and the commonly cited estimate of about 2 million deaths in 1967 shows that the toll had not fallen in the regions without control programs. Estimates for the 20th century alone are uncertain and vary by source, with commonly cited figures starting near 300 million. WHO's own wording is more cautious: it says only that smallpox killed many millions of people before eradication (WHO). Because the records were so incomplete in much of the world, the honest summary is that nobody knows the exact number, only that it was enormous.

Variolation: a dangerous first defense

Long before vaccines, people noticed that survivors never caught smallpox twice. Variolation exploited this by deliberately exposing healthy people to material from smallpox sores, giving a milder illness with fewer deaths than natural infection. It appears to have been used in parts of Asia and Africa for centuries, with accounts of Chinese practitioners blowing dried, ground scabs into the nostril in the mid-1500s.

Lady Mary Wortley Montagu introduced the practice to Europe in 1721. In the same year Cotton Mather argued for it during an outbreak in Massachusetts after learning of it in part from enslaved West Africans (WHO: History of smallpox vaccination). Variolation still carried real risk, because the recipient had true smallpox and could infect others. It cut deaths, but it could also seed new outbreaks.

Jenner and the first vaccine

In May 1796, the English physician Edward Jenner inoculated an 8-year-old boy, James Phipps, with cowpox material. Phipps was unwell for several days and recovered. In July, Jenner exposed the boy to matter from a human smallpox sore, and Phipps stayed healthy (WHO). Jenner published his results in 1801. The word vaccine comes from the Latin vacca, for cow.

By modern standards the experiment was ethically indefensible, and a boy was used as a test subject without any process we would accept. Our companion piece on The Jenner Smallpox Vaccination takes a closer look at what the experiment did and did not show. The core idea held up: a related but milder virus can train the immune system to recognize a deadly one. The mechanics of that training are covered in How Vaccines Actually Work.

Mandatory vaccination began in Britain and parts of the United States in the 1840s and 1850s. Even so, smallpox was still killing more than 2 million people a year in areas that had not eliminated it, according to WHO.

The eradication campaign

The World Health Assembly called for global eradication in 1958, and WHO launched its Smallpox Eradication Programme in 1959. It struggled for years. In 1967 the Organization began an Intensified Smallpox Eradication Programme, backed by freeze-dried vaccine that tolerated heat far better than the earlier liquid form. Commonly cited estimates put the world total in 1967 at roughly 10 to 15 million cases and about 2 million deaths, though the underlying figures are ranges, not exact counts.

The intensified effort cost roughly US$300 million in total, about two-thirds of it paid by the countries where smallpox was endemic (WHO). Measured against the death toll, it is among the most cost-effective public health undertakings on record.

Surveillance and containment

The early plan relied on mass vaccination, aiming to reach most of a population. In practice that was hard to sustain: populations were scattered, roads were poor, and keeping vaccine cold was a constant problem. Teams found that they could stop transmission without vaccinating everyone, provided they found cases fast.

The approach that emerged is usually called surveillance and containment, or ring vaccination. When a case was reported, teams isolated the patient and vaccinated the people around them in widening circles: household, neighbors, then contacts of contacts. The logic is like fighting a forest fire with a firebreak. You do not water the whole forest, only the ground the fire is about to reach. The tactic is most often credited to field teams working under the WHO programme, which D. A. Henderson led, with William Foege among its best-known advocates.

It worked because smallpox spread slowly and visibly. In 1970, an outbreak in south-west India caused more than 1,300 cases and 123 deaths before house-by-house searches and contact vaccination ended it within weeks (WHO). Finding cases was as important as giving shots, which is why village searches turned into a core job for the teams.

The last cases

Smallpox disappeared region by region. It was eliminated in North America in 1952, Europe in 1953, South America in 1971, Asia in 1975, and Africa in 1977. The last naturally acquired case of the severe variola major was a 3-year-old girl, Rahima Banu, in Bangladesh in late 1975. The last naturally acquired case of any kind, a case of variola minor, was Ali Maow Maalin, a hospital cook in Somalia, in October 1977 (CDC: Smallpox history).

The final death came from a laboratory, not from nature. Janet Parker, a medical photographer at the University of Birmingham Medical School in England, was infected with virus grown for research in the laboratory below her workplace. She died on September 11, 1978, the last person known to have died of smallpox (Wikipedia: Smallpox eradication). The Global Commission certified eradication in December 1979, and on May 8, 1980, the 33rd World Health Assembly declared the world free of smallpox.

Why this disease could be eradicated and others have not

Several properties of variola lined up in the campaign's favor. Measles and polio lack some of them, which is why eradicating those diseases has proved harder.

Property	Smallpox	Why it mattered
Animal reservoir	None; humans only	No hidden source of reinfection
Visible symptoms	Distinctive rash in nearly all cases	Cases could be found by sight
Silent carriers	Not infectious before symptoms appeared	Isolation could break chains of spread
Lasting immunity	Survivors protected for life	Fewer reinfections
Vaccine	One effective vaccine, heat-stable when freeze-dried	Could be delivered in remote areas
Spread	Relatively slow, mostly to close contacts	Contacts could be traced and vaccinated

Polio, by contrast, often causes no visible symptoms in infected people, so cases cannot be found by sight alone. Measles is far more transmissible than smallpox. For a detailed look at the latter, see Measles Virus Explained, and for the former see Poliovirus: How It Works and Why It Paralyzes.

Key dates at a glance

Year	Event	Source
About 1350 BCE	Earliest evidence of smallpox-like disease, from Egyptian mummies	WHO
1721	Variolation introduced to Europe by Lady Mary Wortley Montagu; Cotton Mather advocates it in Massachusetts	WHO
1796	Jenner inoculates James Phipps with cowpox	WHO
1801	Jenner publishes results	CDC
1958 to 1959	World Health Assembly calls for eradication; WHO programme begins	WHO
1967	Intensified Smallpox Eradication Programme begins	WHO, CDC
Late 1975	Last natural variola major case (Rahima Banu, Bangladesh)	CDC
October 1977	Last natural case of any kind (Ali Maow Maalin, Somalia)	CDC
September 11, 1978	Janet Parker dies in Birmingham, England	CDC
May 8, 1980	World Health Assembly declares smallpox eradicated	WHO, CDC

Reading the table, the compression at the end stands out. From the first national programs to the last natural case took well over a century of vaccination, but the final push, from 1967 to 1977, took ten years. Intensity and method, not just time, decided the outcome.

Where the virus lives now

When eradication was certified, remaining stocks were destroyed or transferred to laboratories in the United States and the Russian Federation. In 1981, four countries had held variola: the United States, England, Russia, and South Africa. England and South Africa had destroyed or transferred their stocks by 1984 (CDC: Smallpox history).

Today the virus is held in two locations supervised by WHO: the Centers for Disease Control and Prevention in Atlanta, Georgia, and the VECTOR Institute in Koltsovo, Russia. Both are WHO Collaborating Centres, and WHO's Advisory Committee on Variola Virus Research oversees biosafety and biosecurity inspections of the two sites (WHO: Advisory Committee on Variola Virus Research).

Should the last stocks be destroyed

The question of destruction has been argued for decades. WHO first recommended destroying the virus in 1986. The date was set for December 30, 1993, then postponed to June 30, 1999 (Wikipedia: Smallpox eradication). In 1996, at the 49th World Health Assembly, member states decided to destroy the remaining stocks in June 1999, keeping only small research samples at the two designated labs.

In 2002 the Assembly agreed to permit temporary retention of the stocks for specific research, after resistance from the United States and Russia. Retention continues today for essential research, overseen by WHO's Advisory Committee on Variola Virus Research, which has met roughly once a year in recent years; the World Health Assembly endorsed continued retention in 2024 (WHO).

Arguments on both sides are real. Supporters of destruction say the only complete safety is that the virus no longer exists in any freezer. Opponents say that the genome sequences are already published and that research on vaccines and drugs needs the live virus, so destruction would remove a research tool without removing the risk. No consensus has been reached.

Bioterrorism and preparedness

Routine smallpox vaccination ended worldwide after eradication, so anyone born after the early 1980s in most countries has never been vaccinated. Protection from earlier vaccination also fades. The CDC says protection from the traditional vaccine lasts about 3 to 5 years, with a booster needed for long-term protection (CDC: Smallpox vaccines). A large share of the world population is therefore susceptible, a situation unlike anything in the 20th century.

The CDC describes a deliberate release of the virus as unlikely, though possible in theory, since the disease no longer occurs naturally (CDC). WHO says that some governments fear stocks may exist outside the two laboratories, but that it cannot assess that risk, and it helps governments prepare when asked (WHO).

Preparedness rests on three things: stockpiles of vaccine, trained surveillance, and the ring strategy that worked before. Historically the vaccine prevented infection in about 95% of those vaccinated. Protection is strongest before exposure, but it may help if given within three days after exposure and may offer some protection at four to seven days. It does not protect once the rash has developed. That narrow window is why early detection would matter so much in any outbreak. The same logic applies to other outbreak threats, as described in How Pandemics Spread and What Stops Them.

Modern countermeasures

Vaccines: ACAM2000 and JYNNEOS

The classic smallpox vaccine contains live vaccinia virus, not a killed or weakened smallpox virus. It cannot cause smallpox. It is given into the skin and produces a local lesion that serves as visible evidence that the vaccine "took." Complications can be severe in certain groups, including people with weakened immune systems.

Two vaccine types are in play. ACAM2000 is a replication-competent vaccinia vaccine, meaning the virus multiplies at the site of the injection. JYNNEOS is a different design. It is labeled by the US Food and Drug Administration as a "Smallpox and Mpox Vaccine, Live, Non-replicating," approved on September 24, 2019 for prevention of smallpox and mpox in adults 18 and older who are at high risk (FDA: JYNNEOS). Because its virus cannot replicate in human cells, it avoids the risks that restrict replicating vaccines in people with weakened immunity.

Antivirals

Tecovirimat (sold as TPOXX) targets a viral protein that poxviruses use to wrap virus particles for exit from the cell, which limits spread from cell to cell. Because smallpox no longer occurs, human efficacy against it cannot be tested directly. Regulators therefore rely on animal studies, and CDC states that no treatment has been proven effective in people who are sick with smallpox, though some antivirals may help (CDC). The limits of this evidence are a good reminder that eradicating a disease also removes the ability to run the trials that would prove a cure.

Variola and mpox compared

The two viruses are cousins, but they are not interchangeable. The comparison below uses figures from WHO and Wikipedia's variola summary.

Feature	Variola (smallpox)	Mpox
Genus	Orthopoxvirus	Orthopoxvirus
Natural hosts	Humans only	Animal reservoir; person-to-person spread also occurs
Fatality	Up to 30% for variola major	Reported deaths among confirmed cases were about 0.2% from January 2022 to August 2024 (a crude ratio, not a formal case fatality rate)
Eradicated	Yes, 1980	No
Rash	Palms and soles often involved; lesions in step	Often starts on the face and spreads, including palms and soles; number of lesions varies from one to hundreds
Spread	Prolonged face-to-face contact; respiratory droplets	Close contact, including skin-to-skin; contaminated objects; animal bites or scratches

Mpox figures: WHO mpox fact sheet. Smallpox figures as cited above.

Mpox has two clades. Clade IIb caused the global outbreak of 2022 and 2023, and clade Ib has spread person to person in the Democratic Republic of the Congo and then to other countries. WHO notes that mpox emerged in Africa after smallpox vaccination ended in 1980, a pattern consistent with the loss of cross-protection, though other factors also play a part. WHO declared mpox a public health emergency of international concern in May 2022 and again in August 2024; it ended the second declaration on September 5, 2025, while noting that the threat was not over (WHO fact sheet; PBS NewsHour).

What people often get wrong

Smallpox and chickenpox are not related. They have similar names and both cause a blistering rash, but chickenpox comes from varicella-zoster virus, a herpesvirus. The rash patterns also differ, as described above. Our explainer on shingles and varicella-zoster covers the other virus.

The smallpox vaccine did not give smallpox to people. The vaccine uses vaccinia, a related but different virus. It can cause rare, serious side effects, but it cannot cause smallpox itself.

Eradication does not mean no risk. The virus no longer circulates in nature, but it still exists in laboratories, and the genome has been published. Eradication ended natural transmission. It did not end the need for vigilance.

Vaccination did not wipe out the virus alone. Vaccine was necessary but not sufficient. Surveillance, containment, and the persistence of thousands of workers in difficult places ended the disease. Vaccination without reporting would have missed the last pockets of transmission.

The campaign did not run smoothly. WHO launched its first eradication program in 1959, and eight years of limited progress passed before the intensified effort in 1967. The success took restructuring, not just resolve.

The takeaway

Smallpox fell because of a combination of luck and design. Luck came from the biology: a virus with no animal reservoir, a rash that nobody could miss, and immunity that lasted. Design came from people who adapted a plan that was failing, shifted to finding cases rather than vaccinating everyone, and kept at it for more than a decade. The same pieces are missing for most other diseases, which is why the achievement has not been repeated. What remains is a pair of freezers, an unresolved debate about them, and a population with little protection. The next time a rash-causing virus appears, the smallpox playbook of find, isolate, vaccinate the ring, and check again is still the model.

FAQs

Q: Why was smallpox eradicated but not measles or polio? A: Smallpox had no animal reservoir, a distinctive rash that made cases easy to find, no infectiousness before symptoms, lifelong immunity in survivors, and a heat-stable freeze-dried vaccine. WHO also notes it spread more slowly than measles. Polio often causes no visible symptoms, and measles is far more transmissible, so both are harder to stop.

Q: Could smallpox come back naturally? A: Natural return is considered extremely unlikely because variola infected only humans and had no wild reservoir. The realistic concerns are laboratory stocks and deliberate release. The CDC describes a deliberate release as unlikely, but possible in theory.

Q: How long does smallpox vaccine protection last? A: The CDC says protection from the traditional vaccine lasts about 3 to 5 years, and a booster may be needed for long-term protection. Historically the vaccine prevented infection in about 95% of those vaccinated. It is strongest before exposure and may help if given within three days after exposure.

Q: Who was the last person to die of smallpox? A: Janet Parker, a medical photographer at the University of Birmingham Medical School in England, died on September 11, 1978, after being infected with virus grown for research in the laboratory there. The last naturally acquired case was Ali Maow Maalin in Somalia in October 1977, and he survived.

Q: Where is the virus kept today? A: Two WHO-supervised laboratories hold it: the Centers for Disease Control and Prevention in Atlanta, Georgia, and the VECTOR Institute in Koltsovo, Russia. WHO's Advisory Committee on Variola Virus Research oversees biosafety and biosecurity inspections of both sites and has met roughly once a year in recent years.

Q: Does the mpox vaccine protect against smallpox? A: JYNNEOS is approved by the US Food and Drug Administration for prevention of both smallpox and mpox in high-risk adults 18 and older. Both diseases are caused by orthopoxviruses with related surface proteins, which is the basis for cross-protection. Any individual vaccination question should go to a doctor or public health authority.

Q: Why can the smallpox vaccine be dangerous for some people? A: The classic vaccine contains live vaccinia virus, which multiplies at the site of vaccination. WHO says it can cause rare, serious side effects, sometimes fatal, and cannot be given to people who are immune-suppressed. That is one reason routine vaccination stopped after eradication and one reason non-replicating vaccines such as JYNNEOS were developed.

Sources

• World Health Organization. Smallpox health topic and Smallpox questions and answers.
• World Health Organization. History of smallpox vaccination.
• Centers for Disease Control and Prevention. About smallpox, Smallpox history, and Smallpox vaccines.
• US Food and Drug Administration. JYNNEOS.
• World Health Organization. Mpox fact sheet.
• Fenner F, Henderson DA, Arita I, Jezek Z, Ladnyi ID. Smallpox and Its Eradication. Geneva: WHO, 1988 (free via WHO Digital Library).

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