Smallpox debate flares again

URBANA, ILLINOIS — Cathy Laughlin says that we need to keep smallpox around to make the world a safer place. As a senior virologist at the US National Institute of Allergy and Infectious Diseases (NIAID), she oversees efforts to develop an effective smallpox drug and an improved vaccine. Without carefully controlled research on the live virus, it will be harder to develop an antiviral drug and a safer vaccine, increasing the risk of a devastating outbreak if terrorists get their hands on the virus and intentionally release it. Without new antiviral drugs and a better vaccine, the population won't be protected.Al Sommer says that we need to get rid of smallpox to make the world a safer place. Sommer, dean of Johns Hopkins School of Public Health, has never forgotten the months he spent with a Centers for Disease Control (CDC) smallpox control team in Central America in 1972. Three decades after seeing the horrors of the disease at first hand, he says that destroying the last legal virus stocks would help prevent rogue states with secret smallpox stashes from engineering ever more devastating strains. An outbreak could be contained using the available vaccine, and the population would be protected.In the long-running debate over what to do with the world's last confirmed smallpox stocks, Laughlin and Sommer typify the two sides, each with views that are passionately held, well meaning — and diametrically opposed. The debate has shifted and intensified since the September 11 terrorist attacks and the anthrax scare that followed. And now it's heating up again. In March, researchers announced early results on the first oral drug that kills the smallpox virus, and the NIAID announced an extensive research program into defenses against possible bioterrorism threats like smallpox. And next week (13–18 May 2002), the World Health Assembly (WHA) — the international governing body of the World Health Organization (WHO) — will decide whether to give the last known smallpox stocks, which are scheduled for eradication this year, another reprieve. In March, US researchers announced the first potential oral drug for treating smallpox — further fuelling this often-bitter debate. The drug, developed by Karl Hostettler's team at the University of California, San Diego, prevents a related virus, cowpox, from killing infected mice. It also kills smallpox virus in cultured human cells with 100 times the potency of the best current drug candidate, cidofovir. The work was presented at the International Conference on Antiviral Research in Prague.An oral anti-smallpox drug could plug a hole in the defenses against a possible smallpox attack, Hostetler says. The WHO declared smallpox eradicated in 1980, and tens of millions of people have never been vaccinated. The current smallpox vaccine is effective if given within four days of exposure. But there's no drug available to treat people who are not diagnosed and vaccinated in time. And if it progresses, the disease is devastating: the most virulent strains of smallpox kill 30% of their victims and disfigure others.Hostetler says that live virus was critical for their research. They modified cidofovir to form a new drug called HDP-cidofovir that is absorbed from the gut into the bloodstream — unlike cidofovir, which has to be injected. Then a team led by Hostetler's collaborator, John Huggins of the US Army Medical Research Institute for Infectious Diseases in Fort Detrick, Maryland, tested the ability of HDP-cidofovir to kill live smallpox in tests at CDC's Biosafety Level 4 Laboratory in Atlanta. The team has also developed and tested other derivatives of cidofovir. "I personally think that a repository of smallpox strains is a national treasure that should never be destroyed," he says. "That's how we found these drugs and that's how we can make better ones."Laughlin, whose agency helped fund the research, calls the research "very promising but very early," adding that the drug still faces a long series of hurdles before it could be approved as a defense against a biological attack. The drug still has to work against other poxviruses in several animal models of smallpox; it has to be tested extensively for safety in animals and humans. But if it pans out, it could offer a second line of defense after the vaccine, which "is clearly the best protection anybody can get," she says. Even so, the vaccine — a live virus derived from cowpox — is not safe for many people, including patients with immune systems weakened by HIV, cancer chemotherapy, or organ transplants. An effective drug could safely protect these people, Laughlin says.Laughlin adds that the recent results support current US policy, which calls for keeping the virus around as long as it takes to meet a series of research goals, including: two new antiviral drugs that work differently; an improved smallpox vaccine that doesn't sicken those with weakened immune systems; better diagnostic tools, and a good animal model to test drugs and vaccines. "This work ties in directly," she says.Also in March, the NIAID announced an ambitious new research agenda, buoyed by the $1.2 billion increase President Bush has penciled into the 2003 budget to fight bioterrorism. To fight smallpox, the plan calls for expanding vaccine supply, developing better animal models, developing oral antivirals and immunotherapies, comparative sequencing of poxvirus genomes, safety trials for new smallpox vaccines, and a wide range of basic research on poxviruses.Sommer says much of this work can be done without live smallpox virus. As for what can't, the trade-off is worth it to minimize the risk of an intentional smallpox attack, he says. Although secret stocks of the virus may very well still exist in refrigerators somewhere in the world, all known strains of the virus can be controlled with the current vaccine. Instead, it's the many potential bioengineered versions of the virus that could be really dangerous. "The real threat is for other countries to feel like they had to keep up with us and develop a bioengineered virus… that terrorist groups could then get hold of," he says.Researchers should continue to develop drugs and better vaccines as best they can, he says. But the best solution, Sommer argues, is for the US and Russia to go along with international pressure to eliminate the last two legally sanctioned virus stocks, one kept by a Russian government-run laboratory near Novosibirsk, and the other kept by the CDC. Those two stocks had been slated for elimination in 1999, but US and Russian pressure led the WHA to give the smallpox stocks a three-year reprieve, despite the objections of India, Brazil and China, says biological weapons specialist Jonathan Tucker of the Monterey Institute of International Studies, a Washington, DC-based think tank.For now, the debate seems to be tipping toward Laughlin and her allies, who want to keep the virus around. In December, a WHO advisory committee on smallpox met and concluded that researchers need more time to achieve key research goals, including improving a new monkey model, and developing a safer vaccine and an effective drug.When the WHA meets again next week in Geneva, it will decide whether to give the virus another reprieve. The US is pushing for an indefinite extension, until its research goals are met. Most of the rest of the world is pushing for another three- or five-year extension. The WHA could also order the stocks eliminated by the end of this year, although few expect that to happen. At their December meeting, the advisory committee recommended no deadlines, and now it's up to the WHA to decide. The fate of smallpox, and the safety of millions, is in its hands.

Smallpox debate flares again

World Health Assembly to decide whether to keep or destroy deadly virus.

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