Smallpox was declared eradicated in 1980, and no natural case has occurred since 1977. A true resurgence of the disease remains extremely unlikely, but it is not impossible. The variola virus still exists in at least two authorized laboratory repositories, undeclared samples have turned up unexpectedly, and advances in synthetic biology have demonstrated that a closely related poxvirus can be assembled from scratch using mail-order DNA. Meanwhile, most of the world’s population has never been vaccinated, and the fraction that was vaccinated decades ago carries uncertain residual protection. The question is less whether nature will bring smallpox back and more whether human error, security failures, or deliberate misuse could.
Where the Virus Still Exists
After eradication, the World Health Organization allowed two facilities to retain live variola virus stocks: the Centers for Disease Control and Prevention in Atlanta and the VECTOR Institute in Novosibirsk, Russia. These repositories were meant for ongoing research into diagnostics, vaccines, and antivirals. Whether those stocks should be destroyed has been debated for decades. In a survey of health care and life science professionals, about 61% favored keeping the stocks, primarily for future research, while roughly 36% wanted them destroyed, citing bioterrorism concerns.1PubMed Central. Smallpox Still Haunts Scientists: Results of a Questionnaire-Based Inquiry on the Views of Health Care and Life Science Experts and Students on Preserving the Remaining Variola Virus Stocks
The uncomfortable reality is that official stocks may not be the only ones. In July 2014, forgotten vials containing variola virus were discovered at the National Institutes of Health in Bethesda, Maryland. CDC investigators confirmed that at least two of those vials still contained viable virus.2PubMed. Discovery of forgotten variola specimens at the National Institutes of Health in the USA This was a government lab with extensive biosafety protocols. The discovery raised an obvious question: if the NIH had forgotten samples sitting in a freezer for decades, how confident can anyone be that no other labs, governments, or institutions harbor unaccounted-for vials?
Separately, researchers have considered whether variola virus could survive in historical relics like burial sites or preserved tissue. Experimental data on the long-term viability of the virus in such materials is limited, and scientists have cautioned that the unearthing of well-preserved biological material cannot be entirely ruled out as a source of live virus.3PubMed Central. Poxvirus viability and signatures in historical relics This is a very low-probability scenario, but it adds to the overall picture of a virus that, despite eradication, has not been fully contained to two known freezers.
The Synthetic Biology Problem
In 2017, a Canadian researcher working with the biotech company Tonix synthesized horsepox virus from scratch using commercially available DNA fragments. This was the first time anyone had built an orthopoxvirus from the ground up, and biosecurity experts immediately recognized the implications.4PubMed. The De Novo Synthesis of Horsepox Virus: Implications for Biosecurity and Recommendations for Preventing the Reemergence of Smallpox Horsepox belongs to the same genus as variola, and the techniques used to assemble it could, in principle, be applied to variola. The researchers demonstrated that ten synthetic DNA fragments could be transfected into cells and recombined into replication-competent viruses.5PLOS ONE. Construction of an infectious horsepox virus vaccine from chemically synthesized DNA fragments
The variola genome has been sequenced and published. In an era when DNA synthesis can be ordered online, the barrier to recreating the virus is no longer purely technical; it is largely a matter of screening protocols and governance. Updated frameworks for synthetic nucleic acid screening now extend their recommendations beyond just providers of double-stranded DNA to include all entities involved in the sale, use, and transfer of synthetic nucleic acids encoding sequences that contribute to pathogenicity.6PubMed Central. Enhancing Gene Synthesis Security: An Updated Framework for Synthetic Nucleic Acid Screening and the Responsible Use of Synthetic Biological Materials Whether these voluntary industry guidelines are sufficient to prevent a determined state actor or well-funded non-state group from assembling a dangerous pathogen is a matter of active debate. The consensus among biosecurity researchers is that the technical hurdle is real but shrinking, and the screening infrastructure has not kept pace.
How Vulnerable the World’s Population Is
Routine smallpox vaccination ended in most countries during the 1970s and early 1980s. Anyone born after that window has never been vaccinated. A modeling study in The Lancet Infectious Diseases mapped the contemporary global landscape of smallpox vaccination and found enormous variation. At the regional level, the proportion of the population ever vaccinated ranged from as low as 7% to as high as 60%, with parts of Finland, Bulgaria, Japan, and Sweden at the top and areas of Yemen, Colombia, Guinea-Bissau, and Ethiopia at the bottom.7The Lancet Infectious Diseases. The global landscape of smallpox vaccination history and implications for current and future orthopoxvirus susceptibility: a modelling study Large countries like India, China, Brazil, and the United States showed considerable variation even within their own borders.
For those who were vaccinated, the picture is complicated. Official guidelines have generally assumed vaccine-induced immunity wanes to nothing within three to ten years. But longitudinal studies tell a different story. One study tracking vaccinated individuals found that vaccinia-specific antibodies persisted and remained relatively stable for up to 88 years after an initial vaccination, with only about 1.4% of participants having no measurable neutralizing antibody at all.8PubMed Central. Immunity from Smallpox Vaccine Persists for Decades: A Longitudinal Study The catch is that no one knows exactly what level of antibody translates into real-world protection against smallpox, because the disease hasn’t existed since before modern immunological tools were available. Both cell-mediated and humoral immunity are thought to matter, but the exact mechanisms of protection remain unclear, and there is a high degree of uncertainty about how much residual immunity would actually help in an outbreak.9PubMed. Evidence for Residual Immunity to Smallpox After Vaccination and Implications for Re-emergence
Cross-Protection and What Monkeypox Taught Us
The 2022 global mpox outbreak became an unplanned natural experiment in cross-immunity. Researchers collected blood from people vaccinated against smallpox decades earlier and tested it against the monkeypox virus. In one European cohort, about 90% of vaccinated individuals had detectable anti-mpox antibodies, and roughly 70% had neutralizing antibodies. T-cell responses were observed in a smaller group, about 30%.10PubMed Central. Evaluation of Cross-Immunity to the Mpox Virus Due to Historic Smallpox Vaccination A Taiwanese population-based study found mpox-reactive antibodies in 69% of sera, with the prevalence of neutralizing antibodies rising in younger birth cohorts who were vaccinated closer to the cessation of routine programs, from 40% in those born before 1950 to 76% in those born in the 1970s.11Open Forum Infectious Diseases. Persistent Immunity From Historic Smallpox Vaccination and Its Limited Cross-Neutralization of Monkeypox Virus: A Population-based Serological Study in Taiwan
These results are encouraging but come with a caveat. A multicohort study found that cross-neutralization activity correlated with how closely related the target virus was to the vaccine strain. Cowpox virus, which is antigenically closer to vaccinia, was neutralized more effectively than mpox virus. Complement-mediated mechanisms helped bridge that antigenic gap for mpox, but the finding underscores that older vaccines don’t provide uniform protection across all orthopoxviruses.12The Lancet Microbe. Comparative immunogenicity and immune memory of smallpox vaccines and mpox virus infection: a multicohort observational study If variola itself were the threat, cross-immunity from decades-old vaccination would offer some protection in a fraction of the older population. It would not protect the billions of people born since the 1980s.
Some researchers have raised the concern that eradicating smallpox and stopping vaccination created a “vacated niche” in the immune landscape. The growing frequency and geographic spread of human mpox cases has been framed as one orthopoxvirus exploiting that gap. Although mpox is generally less transmissible and less lethal than smallpox, its increasing circulation raises questions about the adaptive potential of orthopoxviruses as population immunity continues to decline.13PubMed Central. Monkeypox: Is the ‘vacated niche’ being filled?
What Happens If Cases Appear
Smallpox spreads primarily through respiratory droplets during close, face-to-face contact. The relative importance of large ballistic droplets versus fine aerosols that can linger in the air was never fully resolved before eradication.14PubMed Central. What was the primary mode of smallpox transmission? Implications for biodefense. This ambiguity matters for planning. If an initial release or outbreak infected a large number of people, secondary spread would still be relatively slow because of the long incubation period and the need for close contact, with hospital workers and household members at highest risk.15PubMed. Smallpox and bioterrorism: public-health responses
The strategy that eradicated smallpox in the first place, ring vaccination, remains the primary containment playbook. Rather than vaccinating an entire population, you identify cases quickly, then vaccinate and monitor their direct contacts. This works because smallpox spreads slowly enough that the vaccine can outrun the virus if surveillance is fast. Modeling of a 1967 campaign in Nigeria and subsequent analyses showed this approach succeeded because of the disease’s relatively slow person-to-person spread.16PubMed Central. Ring vaccination and smallpox control Modern outbreak models reinforce this. A simulation based on current U.S. demographics found that if 90% of patients were isolated within days of symptom onset and 75% of contacts were vaccinated and monitored, cases could be reduced by 82% to 99%.17Clinical Infectious Diseases. Evaluating Public Health Responses to Reintroduced Smallpox via Dynamic, Socially Structured, and Spatially Distributed Metapopulation Models The model also found that preemptive vaccination of health care workers, school closures, and mass vaccination would add only small marginal benefits beyond good surveillance and containment.
Rapid diagnosis is critical for that strategy to work. Real-time PCR assays have been developed that can detect all Eurasian-African orthopoxviruses and simultaneously identify variola virus through its unique genetic signature, distinguishing it from monkeypox, cowpox, and vaccinia with high reliability.18PubMed Central. Real-time PCR system for detection of orthopoxviruses and simultaneous identification of smallpox virus Multiplex assays can further differentiate variola from monkeypox and varicella-zoster virus in a single test run, which matters because the early rash of all three diseases can look confusingly similar.19PubMed Central. Species-specific differentiation of variola, monkeypox, and varicella-zoster viruses by multiplex real-time PCR assay
Modern Vaccines and Antivirals
The vaccines available today are meaningfully different from the ones used during the eradication campaign. Three candidates are in the modern arsenal. ACAM2000 is a replication-competent vaccinia virus vaccine with high effectiveness but carries serious risks, including myocarditis and progressive vaccinia. JYNNEOS, a modified vaccinia Ankara vaccine, has demonstrated about 82% effectiveness in preventing mpox with a far more favorable safety profile. LC16, developed in Japan, shows strong protection in animal models and excellent safety in human trials.20PubMed Central. Safety and Efficacy of Repurposed Smallpox Vaccines Against Mpox: A Critical Review of ACAM2000, JYNNEOS, and LC16 JYNNEOS has emerged as the most promising candidate for widespread use because it can be given safely to immunocompromised people, a group that would be devastated by older replication-competent vaccines.
On the antiviral side, tecovirimat (marketed as TPOXX) is the most advanced option. In nonhuman primates infected with actual variola virus, all tecovirimat-treated animals survived, compared to a 50% mortality rate in controls, regardless of whether treatment began two or four days after infection. The drug also dramatically reduced skin lesions, virus shedding, and circulating viral DNA.21PubMed Central. Efficacy of tecovirimat (ST-246) in nonhuman primates infected with variola virus (Smallpox) It works by blocking a protein the virus needs to wrap its progeny and spread from cell to cell, effectively trapping new viral particles inside infected cells rather than killing the virus directly.22PLOS Pathogens. Tecovirimat: A journey from discovery to mechanistic insights in poxvirus inhibition Two additional antivirals, cidofovir and brincidofovir, have also shown strong activity against monkeypox virus strains in mice, reducing viral replication in the respiratory tract when given systemically or orally.23PubMed. Treatment efficacy of cidofovir and brincidofovir against clade II Monkeypox virus isolates These drugs were developed under the assumption that you cannot ethically run a human trial against actual smallpox, so efficacy data comes from animal models of related orthopoxviruses. The FDA approved tecovirimat under its “Animal Rule,” which allows approval based on animal efficacy data when human trials are not feasible.
The Immunosuppression Complication
One factor that would make a modern outbreak different from any historical one is the dramatically larger number of immunosuppressed people in today’s population. Organ transplant recipients, people on biologic therapies for autoimmune disease, cancer patients undergoing chemotherapy, and people living with advanced HIV represent groups that barely existed or were far smaller during the smallpox era.24Clinical Infectious Diseases. Separate Worlds Set to Collide: Smallpox, Vaccinia Virus Vaccination, and Human Immunodeficiency Virus and Acquired Immunodeficiency Syndrome
A transmission model built for New York City and Sydney estimated that at least 19% and 17% of those cities’ populations, respectively, are immunosuppressed. The model found that the highest infection rates in a hypothetical outbreak would fall on people aged 0 to 19 (who have no vaccine history), while the highest death rates would hit those over 45. Because residual vaccine immunity in the overall population is so low, immunosuppression turned out to be more influential than past vaccination in driving both infection and death rates.25PubMed Central. Influence of Population Immunosuppression and Past Vaccination on Smallpox Reemergence The model assumed that mildly immunocompromised individuals would be twice as likely to develop the deadliest forms of the disease, hemorrhagic and flat smallpox, and that severely immunocompromised individuals would develop hemorrhagic disease at a rate approaching 100%.26Emerging Infectious Diseases. Influence of Population Immunosuppression and Past Vaccination on Smallpox Reemergence This is a genuinely new variable that eradication-era planners never had to consider.
Vaccine Manufacturing and Equity Gaps
Even if effective vaccines exist, getting them where they are needed is not guaranteed. The 2022 mpox outbreak exposed a familiar pattern. High-income countries moved quickly to secure vaccine supplies, while African nations with high transmission rates experienced significant delays. Africa remains dependent on external vaccine sources, constrained by limited manufacturing infrastructure, fragmented regulatory systems, workforce shortages, and restrictive intellectual property regimes.27PubMed Central. MPOX outbreak in Africa: the urgent need for local manufacturing of the vaccine and decolonized health systems A smallpox reemergence scenario would raise the same equity problems on a vastly larger scale. The regions with the lowest historical vaccination coverage are often the same regions with the least capacity to manufacture, procure, and distribute vaccines rapidly.
Vaccine hesitancy adds another layer. Researchers have noted that the dynamics of vaccine refusal are not new. Resistance to the original smallpox vaccine dates back to the early 1800s, and the same basic drivers, uncertainty about need, concerns about safety, and lack of trust, persist today.28PubMed Central. Smallpox vaccination and vaccine hesitancy in the Kingdom of the Two Sicilies (1801) and the great modernity of Ferdinand IV of Bourbon Modern social media platforms add a new amplifier. Modeling work has suggested that if smallpox reemerged, susceptible individuals could be manipulated by disinformation to refuse vaccines, complicating containment strategies that depend on rapid, high-coverage ring vaccination.29PLOS ONE. Countering the potential re-emergence of a deadly infectious disease—Information warfare, identifying strategic threats, launching countermeasures
Why Variola Is Unlikely to Evolve Back Into Circulation
One reassuring feature of variola is its genetic stability. Unlike RNA viruses, poxviruses have DNA genomes with built-in error-correction machinery. The mutation rate of poxviruses works out to roughly two nucleotide changes per genome per year, compared to the dozens that accumulate annually in an RNA virus. Even SARS-CoV-2 mutates far faster.30PubMed Central. What Do We Know About the Smallpox Virus? A Journey Between Clinic and Therapy Phylogenetic analysis of 47 variola isolates from across the globe confirmed that the virus’s large DNA genome evolves slowly enough to produce a robust, stable family tree.31PubMed Central. On the origin of smallpox: correlating variola phylogenics with historical smallpox records
This matters because it means a related animal poxvirus is not going to quietly mutate into variola and start a pandemic. Variola had no known animal reservoir, which is why eradication was possible. Monkeypox and cowpox circulate in animal populations, and their genomes can rearrange in large blocks, but the accumulated genetic differences between these viruses and variola are substantial. The risk of natural evolution producing a “new variola” is negligible on any human timescale. The meaningful risks are all man-made: accidental release, deliberate synthesis, or misuse of existing stocks.
Preparing for a Threat That May Never Arrive
Outbreak modeling consistently points to the same priorities for preparedness. Stockpiling vaccine matters, but it is less important than the operational capacity to detect cases quickly, isolate patients, trace contacts, and deliver vaccines to the right people within days. The surveillance-and-containment approach that wiped out smallpox in the 1970s still works in modern simulations, as long as the public health infrastructure is fast enough.17Clinical Infectious Diseases. Evaluating Public Health Responses to Reintroduced Smallpox via Dynamic, Socially Structured, and Spatially Distributed Metapopulation Models Training health care workers, maintaining laboratory diagnostic capacity, and ensuring that the public understands how ring vaccination works may matter more than the sheer number of doses in a national reserve.
The uncomfortable truth is that preparedness for smallpox doubles as preparedness for other orthopoxvirus threats that are not hypothetical. Every investment in mpox surveillance, rapid PCR diagnostics, antiviral stockpiles, and equitable vaccine distribution also functions as insurance against a variola scenario. The 2022 mpox outbreak was, in some respects, a dress rehearsal, and the performance revealed gaps in manufacturing equity, diagnostic speed, and public communication that would be far more consequential if the pathogen in question were smallpox rather than its less lethal cousin.