Viral eradication and the evolution of smallpox

The control and eventual eradication of the smallpox virus from the wild is one of the most heralded success stories in all of public health. Indeed, smallpox has played a central role in the history of vaccination. Even prior to Edward Jenner's use of the related cowpox virus to protect against smallpox disease, it was known that inoculation with materials from an infectious smallpox pustule or scab (dubbed "variolation") could protect an individual from death due to smallpox, generally resulting instead in a mild form of the illness. Jenner's observation that milkmaids seemed to be protected from the disease--and his use of material from cowpox pustules instead of smallpox--resulted in the development of the science of vaccination. World-wide use of the smallpox vaccine, along with a mass vaccination campaign led by the World Health Orgainzation, resulted in the end of naturally-occurring smallpox on the planet, with the exception of stores of the virus held in the United States and Russia.

This feat is being attempted currently with measles and polio viruses, but it's been much more difficult, and eradication of these viruses may never be attainable. Below I discuss some aspects that are critical to a campaign that seeks to eradicate a disease, and a new paper on the evolution of smallpox viruses.

A number of conditions must first be met to even consider an organism for eradication.

First, the organism must be a pathogen only of humans, and can't have a non-human reservoir. Imagine the difficulty of trying to eradicate something like E. coli or Salmonella, which have a practically endless reservoir in animals and the environment.

Second, the infection must induce long-lasting immunity. An organism that can re-infect a person multiple times, or has a number of different serotypes (such as influenza) is not a good candidate for eradication. Additionally, a vaccine that requires only a single dose for long-lasting protection is also ideal.

Third, to go along with #2, there must be a tool or intervention that stops the chain of transmission between individuals. Though this is often assumed to be a vaccine, it could be an antimicrobial drug, or even a physical quarantine, depending on the organism and its current distribution.

Fourth, there has to be a committment by multiple agencies and countries to organism eradication. This includes not only funds and time but a willingness to work with people in different countries and cultures to bring the eradication plan to fruition.

Fifth, and probably most critical, the disease must be considered important enough to justify the expenditure of time and money. A worldwide effort to eradicate, say, athelete's foot just ain't gonna cut it--it needs to be a disease that's serious in terms of morbidity and/or mortality.

Smallpox met all of these criteria. Notably, it was a scourge of the ages, so the critical point five was easily met. Though related to a number of poxviruses of animals, smallpox is an exclusively human pathogen with no zoonotic or environmental reservoir. The methods of stopping viral transmission--vaccination, isolation of cases, and quarantine of those who were potentially infected--had worked successfully for many years. Natural infection induced life-long immunity, and the vaccination also produced long-lasting immunity. There was an internationally-supported effort to eradicate the disease, and even war-torn countries negotiated cease-fires in order to allow their people to be vaccinated. Additionally, there weren't multiple serotypes of the virus--the related vaccinia virus, used as a vaccine, was able to provide enough cross-protective immunity to protect the vaccinated individual from smallpox infection.

However, the eradication of smallpox took place before the golden age of molecular biology, prior to the polymerase chain reaction (PCR) and certainly before large-scale genetic sequencing. Therefore, smallpox viruses haven't been extensively examined using these methods, until now. A new Science paper has examined the genetics of 45 isolates of smallpox virus, taken from stocks at the CDC and VECTOR (Russia's State Research Center of Virology and Biotechnology) and isolated from patients during the eradication campaign in the 1960s and 1970s, taking a comparative genomics approach in order to examine the evolution and diversity of the strains. They also included a cowpox, vaccinia, and gerbilpox virus.

They found that, overall, there was a relatively small amount of sequence diversity among the isolates, with many of the differences grouping in one region of the genome that had already been suggested to play a role in virulence. This has implications for bioterrorism; if a virus happened to be released, an examination of this region could identify the viral strain relatively quickly (or, alternatively, rule out that it's one of these strains). Additionally, when they examined the proteins produced (the proteome), they found that even for the most divergent proteins, only a few amino acid differences were found between isolates.

Going along with a topic discussed on this blog recently here and here regarding misuse of scientific information (such as genomic sequences) for nefarious purposes, the authors also examined approximately how many mutations would be necessary in order to take one of the animal poxviruses (camel, monkey, or gerbil) and end up with a variola-like virus. The number was fairly substantial (a few thousand base pairs), but they note:

The results indicate that just a few thousand mutations by one of several rapid methods could convert such orthopoxvirus DNAs into VARV (variola virus) DNA. Recently, infectious VACV (vaccinia virus) was recovered by rescuing its genome from a bacterial artificial chromosome containing its DNA. In theory, one could use sequences to synthesize long oligonucleotides to reconstruct VARV DNA. Such rapidly advancing technology makes it important to understand sequence diversity and the proteome so as to develop and maintain countermeasures against malefic-use-created pathogens.

Looking at the phylogeny of the viruses, they grouped generally into three clusters corresponding to geographic areas (Asia, West Africa, and South America), and that they could see some rough differences between isolates, supporting a previous observation that certain viral strains were generally associated with high, low, or intermediate mortality. They also note that the variola viruses were most closely related to the gerbilpox virus, of the ones they sequenced, and speculate on the zoonotic transmission of this virus into the human population. They also note that a large problem with this is that the gerbilpox virus is also contemporary, and of course we lack any isolates from closer to the time when these virus lineages split apart. Another limitation they touched on but didn't explicity discuss is that they only included a very small number of animal poxviruses. A more complete collection, including not only other poxvirus species but also multiple samples of each, may have yielded different results.

Finally, again, these isolates are all from patients, and convenience isolates at that. Of course, with a pathogen as unique as smallpox the investigators have to take what they can get, but that also places a limitation on their conclusions. Still, a fascinating study adding additonal insight into this ancient--and potentially future--scourge.


Esposito et al. 2006. Genome Sequence Diversity and Clues to the Evolution of Variola (Smallpox) Virus. Science. 313:807 - 812. Link.

Image from


More like this

There is as yet no pandemic bird flu vaccine but there are a lot of potential vaccines. The recent fiasco involving Baxter International (here, here) involved one in development. There are many more. They employ old and new technologies and are in various stages, a few in early clinical trials.…
Some were surprised to read that after a pro basketball player swatted a bat out of the air, he had to have rabies vaccinations. This is not a surprise to many medical folks who have had to give rabies prophylaxis after bat exposures. Most of the few human rabies cases in the U.S. are…
Smallpox is, without a doubt, the biggest success story in all of vaccination. The practice of variolation, or the purposeful inoculation of naïve individuals with material from scabs of smallpox victims, was practiced for years prior to Edward Jenner's substitution of cowpox for the smallpox…
The name "dengue" means "breakbone fever" due to the extreme bone pain it causes. The virus is a member of the flavivirus family, which includes the virus that causes yellow fever. Both viruses are arboviruses--viruses that are transmitted by arthropods. In the case of dengue and YF, the…

So, it sounds as if it would take quite a bit of time for (for example) cowpox to mutate into something that could infect humans. Lots of mutations required, and a fairly slowly mutating virus. So smallpox is gone for a while, it seems.

There was some talk, years ago, of the CDC and VECTOR destroying the last of the smallpox virus in deep freeze. Such a move would save money and increase safety. Any updates on such a move?

Ain't gonna happen, Stephen. The Soviet Union manufactured smallpox by the ton during the Cold War, and it's clear that Iraq had a smallpox program at one time as well (though it's obviously been disbanded for a while). Though there was some discussion about destroying the stocks, the fact of the matter is that the virus hasn't been exclusively in the CDC and Vector freezers for some time. Moreover, if there's going to be any development of an antiviral for smallpox, then we need to have some of the disease around in order to test it.

Pick up a copy of The Demon in the Freezer by Richard Preston (of Hot Zone fame). It has some great discussion around both smallpox and the American Anthrax terrorism that occurred a few years ago.

By Tariq Moustapha (not verified) on 14 Aug 2006 #permalink

Cowpox does infect humans, it just isn't as likely to be lethal. The exceptions include people with very poor immune system function and people with eczema (they have a high risk of developing a systemic infection).

Does anyone have references to the religious uproar about the introduction of vaccines as unnatural and immoral, much the same as the reaction to stem cell research and use currently?

So, it sounds as if it would take quite a bit of time for (for example) cowpox to mutate into something that could infect humans. Lots of mutations required, and a fairly slowly mutating virus. So smallpox is gone for a while, it seems.

Not quite. It would take those many mutations to get from one of those to Variola, but it's hard to say whether some other combination of just a few hundred or a few dozen mutations could give it the ability to effectively cause disease in humans.

And I agree with Tariq about destruction of the viral stocks; I think it's unlikely to happen anytime soon, especially in this climate.

You wouldnt have to wait long to find out if it were Vektor variola either. I got to know a bunch of retread Soviet military guys who were put out of work after the collapse and sent here to learn marble mining. Two of them worked at Vektor and told me that this stuff had been sexed up so bad that there was concern that if it were used, it might go native and then come back into Russia as an uncontrollable form. Their favorite was the known type that would give you sheeting and black smallpox. The sheeting one is where all of the skin on your body turns into a big pustule, then you move and your skin falls off and you die shock. I hate to thing what the black stuff was.

Getting smallpox bug is easy. Just dig up a couple of victims graves in full bio suits and you have your virus. Culture it up on animals, get a good pot of the stuff rolling and you have a bioweapon. Against the desires of many virologists that putz Clinton on Presidential order destroyed all but a little handful of vaccine for the stuff and most of it was not viable. I likely though thank God am probably immune to the day I die because I was vaccinated six times as long as its not some wild haired version of it. But my kids arent.
Anyone know where I can get them vaccinated?

Here's a surprise. I moved live variola without my knowlege just after 9/11 for an overnight company by loading it into a DoD cargo flight. They came back six weeks later and told me that I might have been exposed. Huh?

It came in one refrigerator and one backup went with it. I still have the paperwork and a waiver from the DoT for military control. Said, "Live variola, keep refrigerated at all times. In the event of spill, container break or damage call xxx xxx xxxx." Didnt even have the biohazardous labels on it. Kind of makes you wonder.

By M. Randolph Kruger (not verified) on 14 Aug 2006 #permalink

Not cowpox, not camelpox - monkeypox. It's evolving into a human pathogen in sub-saharan Africa right now. No bioterrorism involved, no dastardly secret government plots, just good ol' evolution!

Well, all have *infected* humans at one time or another. What they've not done is *effectively* do so, by becoming maintained in the human population without a zoonotic reservoir needed for re-introduction. I have a post on monkeypox previously that also discusses the current situation with that virus.


People have tried that to culture smallpox--to my knowledge, it's not worked. (Of course, if it had and it was done by "rogue" groups or governments, it's not like they'd broadcast it anyway). It's also been a fear when digging up corpses who'd potentially been infected; that they would accidentally re-introduce the virus. That's never materialized either, to my knowledge.

Randolph, I was vaccinated recently as part of a clinical trial of a new version of the vaccine made in tissue culture. The concept is that it could be produced rapidly. I don't know if I recieved the old vaccine or the new one, but I have my scar. Outside of working in a first responder group, I don't think it will ever be made public except if there is a smallpox attack. The potential side effects are pretty bad, and having to screen the population against them will probably keep the vaccine off the market.

bmkmd: "Does anyone have references to the religious uproar about the introduction of vaccines as unnatural and immoral, much the same as the reaction to stem cell research and use currently? "

I can't find any references right off, but I remember reading about it. There were also religious objections to defibrillation. Tampering in God's domain, you see; bringing folks back from the dead. EVIL!

I don't know how broad any of these were, so one shouldn't make generalizations.

By Michael Suttkus, II (not verified) on 14 Aug 2006 #permalink

bmkmd: "Does anyone have references to the religious uproar about the introduction of vaccines as unnatural and immoral, much the same as the reaction to stem cell research and use currently? "

Here's a bit from the American Society of Anesthesiologists:

"In 1591, Lady Euframe MacAlyane of Edinburgh, Scotland, was bold enough to ask a midwife to relieve the pains of labor. So roundly was analgesia in labor condemned then that she was put to death."

Queen Victoria put the seal of approval on anesthesia in 1853 when she had an anesthetic during the birth of her son Leopold.

Michael Suttkus,

Here's another article from the Lancet which may be relevant

End-of-life: a Catholic view
Markwell H
The Lancet - Vol. 366, Issue 9491, 24 September 2005, Pages 1132-1135