Bioengineering smallpox: Rethinking the unthinkable

Widespread immunization urged — but would it make a difference?

While the United States has taken steps to prepare for smallpox bioterrorism event, the nation remains starkly vulnerable to a genetically engineered strain of the deadly virus. Indeed, if a smallpox attack occurs, a genetically altered strain that could be more virulent or elude the current vaccine actually may be the most likely choice of weapons, the author of a provocative new report argues.

"Most of the literature treats smallpox as a natural disease," says Martin Weiss, MD, professor of medicine at the University of California, Los Angeles. "We have to consider any new smallpox event as being man-made and therefore essentially being a weapon. It will be improved upon because man tends to improve on his weapons. It will not be a natural event. It will be an unnatural, man-made event. We have to assume that someone will try to expand the transmissibility of smallpox."

The former Soviet Union was known to have engaged in an active program to aerosolize bioweapons, including smallpox, Weiss and co-authors of the report note.1 If modified or attached to the appropriate carrier, modified variola virus possibly could remain suspended and infectious for a much longer period than wild smallpox.

"The concern is that [the virus] could be bioengineered so that it could evade our vaccines," Weiss tells Bioterrorism Watch. "Another concern is that it could be made more virulent. Either way would be a problem." He acknowledges the threat may not be immediate, noting that the smallpox genome is complex and its DNA requires the activity of associated proteins to be infectious. However, "it may not be long in coming," Weiss adds.

Indeed, not only is bioengineering possible with smallpox, it apparently is moving from heresy to accepted science. Recently, an advisory committee to the World Health Organization (WHO) recommended scientists be approved to insert genetic markers in the virus to expedite the search for effective drug treatments. The marker would glow under florescent light if a trial drug were ineffective against the pox virus. Weiss says he backs the recommendation, but reaction in the scientific community has been decidedly mixed.

According to published reports, Ken Alibek, MD, PhD, DSc, a former researcher in the Soviet Union’s biological weapons program who defected to the United States in 1992, called it "absolutely the right decision. The bad guys already know how to do it. Why prohibit legitimate researchers to do research for protection."2

Others were aghast at the implications. "We have seen no evidence of a threat that would justify this research," says Sujatha Byravan, executive director of the Council for Responsible Genetics in Boston. "A decade ago, the WHO was planning to destroy the world’s last remaining samples. Today, it is proposing to tinker with the virus in ways that could produce an even more lethal smallpox strain. This is a devastating step backward."

Likelihood vs. plausibility

But as Weiss points out, such genetic engineering of pox viruses already is occurring. Australian researchers increased mousepox virulence by splicing a mouse gene into a laboratory strain.3 Similar constructions might be assembled using human smallpox virus or another pox virus (e.g., monkeypox virus) and human genes.

"We tend to underestimate our enemies," he adds. "It could be an aerosolized virus, a bioengineered virus that we have no vaccine for, or there could be several attacks at once. I don’t want to be overly pessimistic, but I think we should be prepared for any eventuality. If the question is one of likelihood, it is probably unlikely. But the issue is not one of likelihood, it is plausibility. Is such an attack plausible? If it is, the common-sense thing to do is try to [reduce] the risk as much as possible."

Yet Weiss casts a critical eye on many of the assumptions that have guided the nation’s smallpox preparations. Such considerations could prove to be overly optimistic because they do not take into account the many uncertainties regarding transmission and infectivity of the smallpox virus. For example, another misnomer in current thinking on smallpox is that the virus is not a highly infectious disease, he notes. Indeed, review of outbreaks in India and Pakistan in the 1960s showed that each case of smallpox gave rise to not more than three new cases, he found. However, a factor not emphasized in those reports is the extent of existing immunity in the affected population.

"The smallpox [transmissibility] studies were on populations that already had, in effect, herd immunity," Weiss says.

Though emerging data indicate smallpox immunity may last many years after vaccination, those never immunized would be strikingly vulnerable to infection. The immune status of never-vaccinated people (generally younger than 37) probably resembles that of the New World populations that were devastated by smallpox. "The younger population is naive to this virus," he warns. "It would be much like the Aztecs or the American Indians among people under age 36 or 37."

According to U.S. Census Bureau data for 2000, there are some 140 million people younger than 35 in the United States. Though almost 40,000 health care workers have been immunized in recent years, Weiss says the health system could not deal with a competent smallpox attack.

"I think it would be overwhelmed," he says. "If it was natural smallpox, we could probably handle it. But if it is going to be an unnatural event that is amplified by man, I don’t think [the health care system] could handle it."

More vaccinations needed

A great unknown is what level of protection the existing vaccine would afford against a smallpox virus designed to elude it. Nevertheless, the bottom line to many pro-vaccine advocates is that widespread smallpox vaccination of the public and health care community would yield more benefit than risk. The thinking, in part, is that it certainly would protect against wild virus and may at least minimize the impact of a bioengineered strain.

"We would like more widespread vaccination," Weiss says. "I don’t think it should be imposed on the public. There is a long history of people of being resistant to vaccinations. It would create a big political turmoil that is unnecessary. It should be voluntary for people who would like the vaccine. They could judge for themselves, and they can choose if they want it or not."

The risk of side effects and deaths is real, but adverse reactions were relatively few in the recent round of vaccinations among the military and health care workers. In recent data from an ongoing Department of Defense (DoD) study, there was one case of encephalitis reported among 623,244 vaccinations.4 The patient recovered. Fifty cases of contact transfer of vaccinia occurred, primarily in spouses and adult intimate contacts. The lower-than-expected incidence of adverse events may reflect more-careful screening of vaccination candidates, the generally healthy status of the population being vaccinated, the previous vaccination in up to two-thirds of vaccine recipients, and covering of the vaccination site to reduce inadvertent inoculation, Weiss theorizes. Still, there were unexpected coronary problems during the recent round of smallpox vaccinations in both the civilian and military populations.

Ongoing research to improve smallpox vaccine could mitigate the risk, but mass inoculation inevitably would result in fatalities. Depending on the percentage of the population vaccinated, the number of deaths is estimated to be in the range of 125 to 500, Weiss reports.5-7

In addition, a long-forgotten smallpox drug called methisazone should be back on the radar screen given the current threat of bioterrorism, he emphasizes. The agent fell into disuse with the eradication of smallpox, but could be used as prophylaxis to reduce the incidence of smallpox by 30% to 40%.

"It would be better than nothing. I suspect it would be very inexpensive to produce. They used it in India in the 1960s, so it can’t be that expensive. It has no patent protection; it’s in the public domain. I don’t know how expensive it would be to produce it, but it can’t be very much. It would be like a backup insurance policy. In case disaster struck, we would have something available."

On a chillingly practical note, Weiss also recommends stockpiling respirators so that society could continue to function in the aftermath of a smallpox attack. The smallpox virus is 200-300 nm in size, meaning $7 N-100 respirators would be very efficient in preventing inhalation, he notes. The N-95 respirators commonly used in health care settings would be less effective, but still provide some protection. If masks were distributed to the public, it might lessen paralysis of cities and allow continuation of essential services.

"I don’t want to overplay that, because if there is a smallpox attack, no one is probably going to be aware of it for seven or eight days," he says. "So a mask isn’t going to prevent the initial consequences of attack. But once the attack is recognized, if people are wearing masks, they can go out in public with some relative degree of assurance and plus, they would be able to take care of the people who are sick."


1. Weiss MM, Weiss PD, Mathisen G, et al. Rethinking smallpox. Clin Infect Dis 2004; 39:1,668-1,673.

2. Elias P. WHO Board Recommends Allowing Genetic Engineering of Smallpox. Associated Press. Nov. 11, 2004.

3. Jackson RJ, Ramsay AJ, Christensen CD, et al. Expression of mouse interleukin-4 by a recombinant ectromelia virus suppresses cytolytic lymphocyte responses and overcomes genetic resistance to mousepox. J Virol 2001; 75:1,205-1,210.

4. Grabenstein JD, Winkewerder W. US military smallpox vaccination program experience. JAMA 2003; 289:3278-82.

5. Lane JM, Goldstein J. Evaluation of 21st-century risks of smallpox vaccination and policy options. Ann Intern Med 2003; 138:488-493.

6. Kemper AR, Davis MM, Freed GL. Expected adverse events in a mass smallpox vaccination campaign. Eff Clin Prac 2002; 5:84-90.

7. Bicknell WJ. The case for voluntary smallpox vaccination. N Engl J Med 2002; 346:132-135.