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An Uncertain Defense

By W. Wayt Gibbs

How do you test that a human Ebola vaccine works? You don't. The Ebola virus is among the deadliest on earth; in outbreaks last year in the Republic of Congo, 157 of the 178 people infected with it died of hemorrhagic fever. Because it can be exceedingly contagious in aerosol form, the Ebola virus ranks with smallpox and anthrax as one of the most worrisome potential biological weapons. Although there is no effective treatment, recent tests have shown a new vaccine able to prevent infection in monkeys. Clearly, researchers could never intentionally expose human volunteers to the lethal virus. And there are no populations at especially high risk for Ebola, as there are for HIV. So how can doctors determine whether the vaccine works in people?

That question, which applies as well to experimental vaccines for smallpox and anthrax, took on new significance on July 21, when President George W. Bush signed the Project Bioshield Act. The law authorizes the U.S. Department of Homeland Security to spend up to $5.6 billion over 10 years to increase its stockpile of antibioweapons medicines, including drugs that the U.S. Food and Drug Administration has not yet approved as safe and effective.

The secretary of health and human services can now recommend that the president order the distribution of experimental drugs to the armed forces or even to the general populace, should the secretary perceive "a significant potential for a domestic emergency, involving a heightened risk of attack." Although scientific evidence of some kind must suggest that the drugs will do more good than harm, human clinical trials--for decades, the only evidence that has mattered--are no longer strictly required.

The prospect of treating thousands of people with a vaccine or drug only proved to work on animals may seem risky. But the realities of the pharmaceutical market and the lethal character of many bioweapons leave few alternatives. The pharmaceutical industry has already all but abandoned work on vaccines for many of the world's major infectious diseases, such as malaria and tuberculosis, because the people most vulnerable to such illnesses tend to be least able to afford expensive medicines. There is virtually no natural market for vaccines to prevent smallpox (which has been eradicated) or anthrax (which is not contagious) or Ebola (which occurs in vicious but sporadic outbreaks).

So federal agencies are creating a market. "The Project Bioshield law specifies initial stockpiling of Ebola vaccine at about $90 million and a long-term procurement of about $260 million," Vijay B. Samant, president of Vical, observed in an August conference call with investors. Vical is a biotech firm based in San Diego; both it and Crucell, a Dutch company, have won potentially lucrative contracts to manufacture the genetically engineered ingredients in the new vaccine.

"To gain FDA approval, we will have to gather safety data on perhaps 5,000 people," says Gary J. Nabel, director of the Vaccine Research Center at the National Institutes of Health. Nabel's group designed the immunization to have two stages: a DNA primer and a viral booster shot. Both parts contain only minute fragments of Ebola virus, so the vaccine itself could not cause infection. Small human safety trials of just the primer portion, made by Vical, are now under way at the NIH. But recent experiments on macaques have shown that the booster alone led to full immunity against Ebola in less than four weeks. Jaap Goudsmit, chief scientific officer at Crucell, says it remains to be seen how long the protection will last.

That is a question typically answered by a large-scale clinical trial. But a special rule passed in 2002 allows FDA approval even without direct evidence that it works in humans, in cases where subjecting humans to clinical trials would be unethical or infeasible.

A company must first show that the vaccine works in monkeys (or another animal similar to humans). Researchers then have to figure out how the animals' immune systems respond to the optimal dose and find an equivalent dose in humans that generates a similar immune response. Project Bioshield allows the president to waive even that lowered regulation when the nation faces "heightened risk of attack."

It may be years before scientists can determine an optimal human dose for the new Ebola vaccine. That does not mean, however, that it won't soon enter the national stockpile. The Bush administration says that next year it expects to purchase 75 million doses of a new anthrax vaccine that has not yet even completed human safety trials.

Of course, Nabel says, "you can bet there would be follow-up studies if the Ebola vaccine was used in a real outbreak." He acknowledges, however, that "if the vaccine is so good that it aborts infection before the virus induces an immune response, we might not be able to tell who was exposed and who wasn't."