I never understood why smallpox resurrection is so feared. It was heavily suppressed with 19th century organization and technology in developed countries and eradicated even in Somalia with 20th century ones. If it reappeared in NYC somehow, it would be very easy to track given its visible symptoms and quickly eliminated.
Depends on your threat model, I suppose. I expect any accidental outbreak to pretty much play out that way.
However, if it were weaponized, I'd expect it to be distributed more widely and released more-or-less simultaneously in hopes of overwhelming the system.
This still seems kind of suicidal for a nation state. They could vaccinate their own populace first, but then they might lose the element of surprise.
That leaves terrorists, who are mainly trying to intimidate people, and only incidentally cause damage to do so, making them less threatening than they would like to appear.
Advancing biotech makes such attacks more likely as it lowers the bar, but it also enables better responses to threats, like the sewage monitoring and rapid vaccine development we saw during the COVID-19 pandemic, disappointing as the government's performance was.
I agree that most of the risk from smallpox comes from a weaponized strain. Given what we know about the Soviet bioweapons program, I think any form of weaponized smallpox released would be engineered to bypass existing vaccines. This would make getting the smallpox vaccine in anticipation negative EV.
Also, wasn't there a theory that the smallpox vaccine gave partial protection against HIV?
I both think and hope that you're right and a smallpox outbreak could be easily contained, but I'm not confident enough in this to be unconcerned. If large amounts were released to overwhelm the system, this could cause a lot of death, particularly in urban areas. I would be particularly concerned if I lived in a crowded slum/favela, because I imagine smallpox could rapidly spread through the populace before quarantine efforts could do much.
Another thing is that smallpox symptoms appear flu-like for the first several days of the infection. During this period it's quite contagious. It's plausible that, in the case of smallpox being released, people will assume it's just a respiratory illness ("Whew, looks like I tested negative for Covid!") and spread it before the characteristic pustules appear and the authorities react. (Disclaimer: I am not an epidemiologist, merely a concerned citizen)
Good to know. But far from clear to me that this passes the risk/benefit analysis. You might need a booster as often as every 2 years to maintain immunity. There are many other infectious diseases we don't routinely vaccinate for, but for which vaccines exist. Rabies, for example, is almost universally fatal, and you can get it from an infected bat bite in your sleep that's too small to notice. Why not get them all?
Well, they have costs. Getting them all would literally be expensive in money, time, and they have side effects, some worse than others. The recommended set is recommended for reasons. Beyond that, it's probably only worth it to get additional vaccines if you're going to be at risk for something in particular.
According to the CDC, vaccination lasts 3-5 years, with protection waning after that. How fast the protection decreases is not entirely clear, especially on the scale of decades, but I did find this Scientific American article claiming that mortality rates were reduced from 52% among the unvaccinated to 1.5% for those vaccinated within ten years and to 11.5% for those vaccinated between 10 and 20 years prior in a study. This article suggests that vaccination during infancy reduced the mortality rate to under 5% for 30 years, and the mortality rate for vaccinated individuals was never above half that for unvaccinated individuals of the same age range. Similarly, mild cases of smallpox are far more common among infected vaccinated individuals than unvaccinated individuals. All this is to suggest that vaccination confers some kind of lifelong protection, at least statistically.
As for the difficulty, I would like to emphasize that this was very easy for me to do. Getting the appointment and vaccine took about 2 hours, and they were completely free. The swelling was a tad annoying but not too bad.
What most people call smallpox on this topic is three distinct things. There's smallpox the disease. There's the variola virus that causes smallpox. And then there is weaponized smallpox virus.
The virus could mean frozen samples, the 14kb of data or metric tonnes of physical material.
The WHO's DNA sequence is NOT widely available. The sequence is tightly controlled by the WHO and researchers are not allowed to access more than a small percent of the whole sequence, I believe it's 20%. Their copy isn't that important except as potential disinformation vector.
Weaponized smallpox could just be "hot" strains. The Soviets ran a global campaign collecting particularly bad strains of any disease they could get their hands on. It was detailed in Alibek's book Biohazard, although Alibek is not the most reliable source.
If a state is committed to hosting an offensive bioweapons program, they have also morally committed to the indiscriminate use of a weapon of mass causality. Richard Preston notes in his book The Daemon in the Freezer they'd likely be morally willing to test that strain on their own people, and down that slippery slope is a very low methodology that requires only very rudimentary science and zero ethics to optimize a new strain.
When the lead scientists in the Soviet bioweapons programs defected in 1993, we learned a lot about what they had been up to, which included field testing aerosolized versions of smallpox and producing metric tones for distribution by missiles. According to US intelligence, as late as 2021 the bioweapons program had survived despite attempts to destroy it due to careful efforts of Russias intelligence services across various political regimes. The current head of state is an intelligence officer, which eliminates those potential political conflicts.
Anyone who understands the extent of the Soviet program begins to understand why we likely won't ever be able to say smallpox is eradicated with certainty.
The Soviets had an island complex for field testing in the Ural Sea called Aralsk-7. They had a documented bioweapon leak in July 1971 that resulted in an nearby outbreak. The outbreak was ended by a mass vaccination campaign, the suspension of all regional transport and (I think) mass quarantine. Occasional Paper 9 of the Center for Nonproliferation is a full report with commentary by relevant experts.
You conflate what would happen in a typical outbreak with what would be likely to happen in an biological attack. Since this weapon requires secrecy and can only be used once, an attacker would want to disperse a large amount at a night time event, or series of them. The bigger the event the better, the more events the better. Soviets optimized for the D50 value of the payload material required, which is the least amount of material needed to infect half the people in a one kilometer square.
Other factors that would tend to increase the impact of an attack would be if our national security apparatus and healthcare system was on the back foot―displaced or dismantled. Think: fire all the epidemiologists at the CDC level of crazy. If society had been primed with disinformation about masks and vaccines, that would aid the attack too.
If your argument is for pre-vaccination, JYNNEOS was specifically designed to be much safer than ACAM2000. In the wake of 9/11, a 2002 vaccination campaign to vaccinate healthcare workers lead by DA Henderson failed partly due to the fact that ACAM2000 is one of the most dangerous vaccines we have. ACAM2000 will only be used after an attack, and it is only available from HHS. Henderson has a page in his 2009 book that appears to describe deliberate stalling and sabotage of his 2002 campaign over paperwork for equipment manufactured in the '50s regarding the number of needle jabs.
Henderson and Richard Preston were instrumental in the creation of the Strategic National Stockpile of mostly smallpox vaccines. Preston wrote the book that scared President Clinton in 1998, and when Henderson debriefed Soviet bioweapons scientists he immediately recognized the danger of a virus we had both zero immunity and zero production capacity for.
Smallpox is idiosyncratic as a virus because of how specialized it is in lethality and transmission pathways specific to humans. It simply cannot be compared with diseases like polio, measles, or anything we actively maintain heard immunity for, because we stopped vaccinating for it sixty years ago. Smallpox is way more contagious than ebola or anthrax.
Smallpox has a high reproductive number, six people become infected on average for every case, very similar to COVID. The global population has effectively zero immunity to it, also much like early COVID. Baring mass vaccination or sustained mass quarantines, the death toll would likely be near the case fatality rate multiplied by the susceptible global population.
For comparison, measles has a reproductive number of 20, so herd immunity level is 95%. The US maintains a vaccination rate around 93%, making the effective reproductive number around to 1.6 (very slow). Measles is only 1% fatal. So a full scale measles pandemic would be expected to kill 0.02% of the population in the US. If you repeat the above logic in a table for every disease, you will understand why no disease is remotely like smallpox in the potential for genocide.
On the range of lethality, with modern gene editing, inserting a single gene into a live virus is trivial and has been shown to cause drastic changes in vaccine resistance and lethality. This was discovered accidentally in a mouse/mousepox model by Ramshaw & Jackson.
Classical wild smallpox did have a one hundred percent kill rate on some Caribbean islands in the Americas during the genocides caused by European settlers. A weaponized smallpox strain developed with high lethality would tend to mutate back to the wild fatality rate in a pandemic, but it would likely become more contagious at the same time, as with COVID. The math for the end of a highly lethal outbreak is a bit wonky because the population changes drastically, increasing the concentration of people in a simple model.
For dated events in history, the Soviet Union has actively spread disinformation in about every major disease event since 1947, which usually center on rumors of an offensive US bioweapon program. It was the Soviet Union that proposed the global "eradication" of smallpox at the UN General Council in 1958 after a nine year absence. The US stopped vaccinating children in 1971. All major countries signed a bioweapon ban treaty in 1975. Access to ACAM2000 was restricted in the 1980s, no one was allowed to be vaccinated for smallpox, creating a totally naive population. Increased awareness around this specific threat coincided with the rise of anti-vaccine movement in 1998. There was a failed vaccine campaign (for HCPs) in 2002. In 2020-23 persistent COVID disinformation radically altered public views around masks and vaccines specifically. There were extensive efforts throughout 2025 into 2026 to actively dismantle both domestic and global public health, as well as our national counter-terrorism defenses. Specifically, the US DHS developed and maintained labs to monitor for pathogens at large events to give us a two week head start in response to an incident, and I believe those labs have been mothballed for the ICE roundup project. The rapid acquisition of concentration camps is obviously not good.
Hindsight is 20/20, and you were obviously wrong to get vaccinated in 2023, because we can all now agree you were too early.
Although it's been a while since I wrote this, and I don't remember exactly what was going through my head when I did, I think I can clarify some of the topics you've brought up.
You conflate what would happen in a typical outbreak with what would be likely to happen in an biological attack.
I certainly agree that there are relevant and important differences between an accidental release of smallpox and an intentional release! I think the main point I was trying to make here was that both are scary, and, at an individual level, vaccination protects against both.
The WHO's DNA sequence is NOT widely available. The sequence is tightly controlled by the WHO and researchers are not allowed to access more than a small percent of the whole sequence, I believe it's 20%. Their copy isn't that important except as potential disinformation vector.
That's interesting! Could you provide a reference for that? I can't seem to find any corroboration. My guess is that the 20% figure actually refers to the amount of the genome that scientists are allowed to have synthesized, not how much of the genome data they can access.
Hindsight is 20/20, and you were obviously wrong to get vaccinated in 2023, because we can all now agree you were too early.
Sorry, could you clarify? Are you claiming it's better to be vaccinated now than it was back then? Or was this kinda tongue-in-cheek?
It is scary, even if you're vaccinated. Fear is great for motivating people, but not really great for getting people to act rationally in an emergency. Invoking terror would be part of the objective of the attack, and being clear headed and rational can mitigate the impact.
To think about what would happen in a disease event, you would want to know the Reproductive Number (R), the incubation period, and the fatality rate. I think those are about 6, 14 days and 30% respectively. Herd immunity would occur when around 5 in 6 people were had immunity, then the event would stop.
One case of smallpox would be an international emergency, but something that could be managed.
If a group managed to suspend CDC testing, and DHS monitoring, and infect a few million people, that scenario could ONLY be managed with mass quarantine.
DA Henderson wrote a guide for healthcare professionals for what to do in the event of a manageable smallpox bioterror event with more clinical information. Care would likely not take place in hospitals for very long. There is also a chapter on mass quarantine in the same issue.
On the fraction of DNA available, The WHO says:
No laboratory, other than the designated smallpox WHO global repositories, shall be permitted to hold variola virus DNA representing more than 20% of the variola virus genome at any one time (2).
Fragments of variola virus DNA for diagnostic kits, not exceeding 500 base pairs in length, may be freely distributed for use as positive controls or standards in diagnostic kits, providing collectively they do not exceed 20% of the total genome size held by any entity (4, 5).
https://iris.who.int/server/api/core/bitstreams/474cb0d6-76d1-42c1-a39b-e167b0e770ee/content
In Richard Preston's The Demon in the Freezer, Superpox Chapter, he says it's limited at 10%, but he wrote that book in 2002, and the current restrictions are from 2016.
The existence of the common DNA sequence with the WHO just will just give bad actors material for conspiracy theories and state propaganda narratives.
Sorry, could you clarify? Are you claiming it's better to be vaccinated now than it was back then? Or was this kinda tongue-in-cheek?
Yes, a little tongue-in-cheek. I think the jury is still out on how effective the JYNNEOS vaccine will turn out to be. A recent vaccine might presumably provide more protection, but it's way better than not being vaccinated at all.
Even without vaccine, there is a lot of hope for managing an event with masks, handwashing and strict quarantine protocols. Good information (as well as disinformation) can travel much faster than a virus.
A common figure cited for the death toll of smallpox is 500 million, as in the title of the excellent essay and adaptation. Half a billion human lives lost is difficult to internalize. The more you think about it, the more it becomes clear that its eradication was among humanity's greatest accomplishments. However, if you look further you'll see that this figure refers to the deaths due to smallpox in the century preceding its eradication—approximately the time period of 1880-1980—not the total number of humans smallpox killed. We don't know how many people it killed before then. It's important to remember that vaccines were developed in 1769, so 500 million deaths happened long after we started to win the war. We have less knowledge of the casualties before then, when we had far less effective defenses. One thing is certain, though—it was an absolutely dreadful illness and we should be grateful that it no longer exists in the wild.
If smallpox is eradicated, what's there to worry about? Unfortunately, quite a bit. Smallpox still exists in some laboratories—two that we know of, VECTOR in Russia and the CDC in the United States. The last person to die of smallpox contracted the disease via a lab leak in the United Kingdom (although the UK later destroyed all of their laboratory smallpox samples). In 2014, a few vials containing viable smallpox were found in an old FDA facility in Maryland. In 2013, a few smallpox scabs were found in an envelope in New Mexico. Smallpox may be present in other locations, and we just don't know it. There exists some claims that it is possessed by North Korea, for example. If you're in the mood to appreciate the fragility of our containment systems, hop over to the Wikipedia list of laboratory biosecurity incidents.
Perhaps the most worrying possibility yet is that of smallpox's resurrection. The genome of smallpox is publicly available and well-known. Likewise, the technology for synthesizing a viral genome is also well-known. Horsepox, which is similar enough to smallpox to be used in vaccines, has been synthesized from scratch in a laboratory. Horsepox has a genome slightly larger than smallpox, and was synthesized for approximately 100,000 USD by a university in Canada. Likewise, DNA printing technology is becoming increasingly cheap. It is already possible for a motivated and skilled group to create smallpox for whatever reason they want, and the level of motivation and skill required gets lower every year.
Fortunately, it's possible to get the smallpox vaccine even if you don't live in a country that carries out regular vaccinations in 2023. This is because vaccines that work for monkeypox also work for smallpox. In fact, monkeypox vaccines are nothing but rebranded smallpox vaccines! In the US, there are two main choices for monkeypox vaccines: JYNNEOS and ACAM2000.
JYNNEOS is a new vaccine. It works by infecting the user with a weakened but viable vaccinia virus, which is closely related to smallpox. It is taken in two doses 28 days apart. It's generally more mild than ACAM2000, the other vaccine, and doesn't leave a scar. It isn't as well-established as ACAM2000, though. It's also not recommended for people with any in a long list of preexisting conditions.
ACAM2000 is an older vaccine, meant primarily for smallpox. Before the monkeypox outbreak, it was primarily taken by researchers working with smallpox and other related viruses (called orthopoxviruses). It's quite similar to traditional smallpox vaccines in that it uses a live vaccinia virus. It's approximately as effective as the vaccines historically used to prevent smallpox are. However, this also means that ACAM2000 is not a mild vaccine. It's not pleasant, leaves a scar and has a high chance of side effects compared to other vaccines. It can cause serious heart problems called myocarditis and pericarditis, which is observed in about 1 in every 175 persons. These seem to get better after a few weeks, but in some cases can last longer or even be fatal. There is a long list of conditions that someone should not take the vaccine if they have.
Because of my concerns, I took the JYNNEOS vaccine a few months ago. All I had to do was find a site and ask for a monkeypox vaccine. I experienced swelling in my arm afterward, but other than that there were no symptoms. The shots were completely free, as they all are within the USA. The clinic I visited did not provide ACAM2000 vaccinations, and I get the impression that these are generally less available today. I consider my choice to be a good one; you may want to consider whether the threat of smallpox today makes getting a monkeypox/smallpox vaccine worth it.
A few frequently asked questions
If someone wanted to resurrect smallpox, couldn't they modify it to be vaccine resistant?
Possibly. This would likely be more difficult than simply creating the smallpox genome and infecting a cell with it. I don't have a great sense of the odds that an attack would look like this. Researchers once modified mousepox such that vaccination mattered less, but even then vaccinated mice had greater odds of survival than unvaccinated mice. This is a subject that could potentially generate infohazards, so please exercise caution while brainstorming about this.
I was born in China and have a scar on my arm from a vaccination. Was this for smallpox?
Probably not. China doesn't carry out smallpox vaccinations anymore, but does use a scar-forming TB vaccine. This is likely what that scar is from.
If I got smallpox, how likely will I be to die?
Historically, the case-fatality rate for unvaccinated people with smallpox is about 35%, and about 6.5% for vaccinated people. These estimates are taken from historical data, when resistance to smallpox through natural means was more common and healthcare was worse, so it's difficult to say.
What is it like to get smallpox?
According to Wikipedia, it starts out with flu-like symptoms, muscle pain, general discomfort, headache and fatigue. You might feel nausea and backaches as well, for about 2-4 days. Lesions will appear on your mouth, tongue and throat, which will quickly grow and rupture. A day or so after this, you'll get a rash on your skin, which will spread around your body. Most likely, you'll wind up with ordinary smallpox if you're unvaccinated. This will turn your rash into a bunch of pimples (papules), which will fill with fluid for a few weeks. After this, they'll deflate and flake off, forming scars. This is the most common type, but the first chapter of the book Smallpox and its Eradication has a lot more detail, although it's not for the faint of heart.
Are there vaccine stockpiles?
Yes. Many countries have smallpox vaccine stockpiles, and the WHO has access to millions more for international use. The distribution of these vaccines during an emergency may prove to be difficult, however. The Covid pandemic taught us that taking the right measures in time can prove to be very difficult. Still, this would make a smallpox outbreak much easier to contain than an outbreak of a similar disease without an existing vaccine.
Thanks to (in alphabetical order) Alana, Andrew, Chris, Derik, Kirke, Rio, and Sofya for helpful discussions.