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.

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6 comments, sorted by Click to highlight new comments since: Today at 8:09 AM

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?

[-]joec7mo1-2

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.

[-]joec7mo50

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.