By Declan Butler of Nature magazine

Health ministers from the World Health Organization's (WHO's) 193 member states will next week debate when to destroy the two last known remaining stocks of the virus that causes smallpox, a scourge that was eradicated in 1980.

Many scientists argue, however, that the variola stocks should be maintained, perhaps indefinitely. The stocks are helping the development of new countermeasures such as drugs, vaccines and diagnostics in case smallpox should reappear, and may also allow researchers to explore the impact of smallpox on the human immune system, providing insights into other diseases such as AIDS.

After smallpox was eradicated, the WHO quickly reached a consensus that existing lab stocks should be destroyed to eliminate the risk of accidental release, and a deadline of 1993 was set. By 1984, stocks from 74 laboratories had been either destroyed or transferred to the two WHO-sanctioned repositories-the US Centers for Disease Control and Prevention in Atlanta, Georgia, and the Russian State Research Center of Virology and Biotechnology in Koltsovo, near Novosibirsk.

Many developing countries that would probably bear the brunt of any accidental release have long backed the destruction plan. But the WHO has repeatedly pushed back the deadline under pressure from developed countries, including the United States, who want to continue research on the virus. At a meeting in Geneva, Switzerland, next week, the United States will seek a further reprieve for the stocks.

The disagreement stems from big differences in the perception of risks and benefits among many developed and developing countries, says David Heymann, chairman of the board of UK Health Protection Agency, and former Assistant Director-General for Health Security and Environment at the WHO, where he also oversaw efforts to eradicate polio.

Many poorer countries view smallpox research as a potentially dangerous luxury, he explains, whereas developed countries' main concern is to continue research that would protect against the consequences of a deliberate release by rogue states or terrorists, who may have access to undeclared stocks.

"There are adequate, if not overwhelming, reasons to be concerned that the two repositories that are under debate right now are not the only places in the world where live smallpox virus still exists," says Nils Daulaire, director of the Office of Global Health Affairs at the US Department of Health and Human Services, and head of the US delegation to the Geneva meeting. "As long as that possibility exists, I think the world is a much safer place with the development of these countermeasures." The United States remains committed to ultimate destruction of the stocks, he adds: "If we knew for a fact when we would have these smallpox vaccines and antivirals fully developed and fully licensed, we would have no problem with a clear timetable for destruction."

Many scientists also argue that destroying the stocks would do little to protect the world from smallpox, because it is now possible to recreate the virus from its genome, which was sequenced in 1994. Only a handful of labs have the skills and resources to do so, but it is likely to become easier over time as DNA-synthesis machines become faster and cheaper.

Pox progress

The WHO last considered destroying the lab stocks in 2007, when it postponed the decision pending an assessment of whether more research on the live variola virus was needed. The WHO has emphasized that science alone cannot justify retention, and that any research must have tangible public-health benefits.

The review panel convened to address the matter was not asked to assess whether the stocks should be destroyed, although its report, published last December, made a strong case for continued research. Perhaps reflecting the debate's complex politics, the WHO asked a separate expert panel (AGIES), made up largely of public-health experts from developing countries, to review the scientific report and recommend whether further research was warranted. They argued that it is largely not.

The AGIES panel's "perception was flavored by its public-health perspective on scientific arguments", says Grant McFadden, a poxvirus researcher at the University of Florida in Gainesville and a member of the scientific review panel. He believes that the risks of accidental release are low compared with the scientific and public-health benefits.

McFadden points out that the past decade has seen much progress in smallpox research, in particular the development of two new drugs (which have not yet been licensed). Current vaccines are effective, but are unsuitable for people with compromised immune systems, including people with HIV.

The key problem for research on smallpox is that there is no good animal model for the disease. "Human smallpox doesn't cause disease in non-human primates that resembles the human disease," says McFadden. Infections of other poxviruses in their natural hosts provide more realistic, yet still imperfect, models.

Because clinical trials of new drugs and vaccines for the disease are impossible, the US Food and Drug Administration and other regulatory agencies currently demand that vaccines and drugs show efficacy in animals challenged with live smallpox. The WHO's AGIES panel argued, however, that the regulatory system should be changed to allow licensing of smallpox drugs and vaccines on the basis of multiple animal surrogates, using various poxviruses in their natural hosts. The only remaining need for the live virus was to test the efficacy of drugs in vitro, it said.

But the entire debate over regulatory needs may be moot, says Jonathan Tucker, a biosecurity researcher at the Federation of American Scientists in Washington DC. Any likely use of drugs or vaccines against smallpox would come under emergency regulatory provisions that allow the use of treatments that have not been completely tested.

The outcome of next week's meeting is difficult to predict. WHO resolutions are not legally binding under international law, so the body usually seeks to pass them by consensus, with very few going to a vote. "I'm very confident that at the end of the day there will be a resolution accepted by consensus that will maintain a program of research and that will call for a review of progress in a number of years," says Daulaire.

If a vote did result in a decision to destroy the stocks, the United States and Russia would be left in a difficult position, says Tucker. They could comply with the WHO's request or defy it-or perhaps, more worryingly, they could be tempted to maintain their stocks covertly.

This article is reproduced with permission from the magazine Nature. The article was first published on May 13, 2011.