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Smallpox: U.S. Army Derives Controversial Primate Host, Possible Bio-Defense Breakthrough By David Ruppe The technique is controversial, however, because it provides a justification for continued testing using the highly contagious and deadly disease, which many would like to see fully eradicated. Skeptics also question its usefulness in simulating the conditions under which a smallpox vaccine for humans would be tested. The primates were subjected to an extraordinarily high concentration of a potent strain of the variola virus. The dose, much higher than would result from a biological weapons attack, was needed to kill the monkeys, but the monkeys died too quickly to mirror the progression of the disease in humans. “My feeling is actually we’ve achieved what they said was unachievable,” said Peter Jahrling, a scientist at the U.S. Army Medical Research Institute for Infectious Diseases at Fort Detrick, Maryland. “We’ve achieved a lethal disease course when they said it was not possible.” He nevertheless acknowledged the model is a work in process, and added, “the folks who were a little bit upset with us for achieving the unachievable are now gleefully rubbing their hands and saying, well, what the hell good is that, [the dosage] is hardly a realistic disease course and are seeking to discredit the model.” Jahrling said his testing data was received with skepticism by D.A. Henderson, who heads the Health and Human Services Department’s Office of Public Health Preparedness. Henderson, revered for directing the World Health Organization campaign that eliminated smallpox worldwide in the 1970s, now heads the Bush administration’s biological defense efforts. The military scientists hope to return soon to the maximum containment laboratory at the Centers for Disease Control and Prevention — the only place in the country where the live virus can be tested — to try a lower concentration with the hope it will yield a more protracted disease course. “We can certainly moderate that disease course over time,” Jahrling said. The military scientists hope to refine their technique and soon publish their results in a peer-reviewed article in the magazine Science. Time Was Running Out The discovery may have helped buy the military some time against pressures to eliminate the U.S. variola stocks. A World Health Organization ad hoc committee, which included Jahrling, voted to allow such testing of the live virus, but only through the end of this year, when it said the world’s final remaining smallpox stocks should be destroyed. Research on safer vaccines that would require access to the virus was not warranted, it concluded. Committee members cited difficulties in finding a primate host for efficacy testing. In a major reversal, however, the WHO committee said earlier this month the United States and Russia should continue to keep their smallpox specimens for use in developing new vaccines and antiviral drugs (see GSN, Jan. 18). In the wake of the fall anthrax attacks, the Bush administration already had unilaterally announced it would indefinitely retain variola stocks (see GSN, Nov. 16, 2001). New Vaccines Preferred The lack of a proven primate host has posed a significant obstacle to efforts to test and develop improved smallpox vaccines and anti-viral drugs. The only vaccine currently certified by the Food and Drug Administration for use is called Wyeth Dryvax. It was proven effective in the successful 1960s and 1970s global effort to rid the deadly virus from the human population worldwide. Dryvax also was found, though, to have caused serious side effects in a significant percentage of the millions vaccinated and particularly in those with suppressed immune systems. Massive administration of the vaccine to the U.S. population, either for preventive or responsive purposes, could kill many dozens of people and cause larger numbers of encephalitis, experts have said. A U.S. company was contracted for $428 million in November to increase U.S. vaccine stores to cover the entire population (see GSN, Nov. 29, 2001). There are so far no anti-viral agents proven effective in treating smallpox, and development of them is considered a costly, time-consuming project. U.S. and foreign laboratories have developed some promising safer vaccines. An army vaccine has passed safety and immunogenicity testing. Before they can be used, however, they must meet FDA standards for efficacy — contained in a draft rule — meaning they would need to be tested on some animal, preferably as close as possible to humans, and preferably against the actual virus rather than a cousin. A separate disease, monkeypox, did cause a similar disease to human smallpox in monkeys, and the Dryvax and new U.S. military vaccines proved effective against it. The monkeypox tests, though, are considered less satisfactory for meeting FDA standards. Proven Host Unavailable The smallpox disease has only been found in humans. Some scientists have believed it impossible to fatally infect other vertebrates, but primates could be temporarily infected by it. Jahrling and colleagues previously sought a way to create a successful primate host, but attempts to fatally aerosolize — the probable form of a terrorist attack — primates with the virus were unsuccessful until last year. Exposing the monkeys to the highest aerosolized doses they could muster (100 million infectious particles per cubic centimeter), all they could produce was a very modest infection, some fever, a few pustules, and “a headache, I presume, since they didn’t tell us,” Jahrling said. All recovered. With the WHO-prescribed time running out for further studies, Jahrling says he and his colleagues decided, “Let’s throw everything we’ve got at it.” A Too-Rapid Death Doing so, they developed data last fall showing they could give cynomolgus macaques fatal smallpox by subjecting them to both aerosolized and intravenous doses, concentrated at 1 billion particles per unit, of a potent strain. “What we did is we reasoned we could put in tenfold higher a dose if we gave it by an intravenous route as well as the aerosol,” he said. They also decided to use a strain of the virus used in the Russian weapons program called “India 1.” The result, was a “very rapid and fulminant disease with almost all of the animals dying very acutely between four and seven days after exposure,” said Jahrling. Fourteen of the 16 monkeys tested died, and “the other two wished they had,” Jahrling said. The concentration also worked when it was just injected, but, again, the animals died too quickly to simulate the usual expected human progression of smallpox. In the natural course of the disease, the virus first sits in the mucus of the respiratory tract and incubates for about 12 days. A vaccine, if not previously administered, is best given in the first four days. If not successfully vaccinated, the person may eventually become extremely sick as the virus enters the blood stream and organs. An estimated 30 percent or more people exposed to smallpox die of the disease. “What we think we’ve done is sort of eclipsed that first phase and gone directly to the second phase. So we’ve given them an artificial veremia,” Jahrling said. With the lower concentration producing no fatalities, there is a concern a middle ground will be hard to find. Jahrling is optimistic he can get there. Concentrations, Progressions Unrealistic? Still, that will not answer criticism that the concentrations necessary for fatalities are somewhere on the order of 1 million times higher than what would be found in an outbreak. “It seems to me that the huge dose required may subtract from its usefulness,” said Barbara Hatch Rosenberg, a molecular biologist who runs the Federation of American Scientists’ chemical and biological arms control program, and who opposes continued live variola research. The high doses required to kill the monkeys may overwhelm a vaccine that might work against a more realistic concentration, she said. Another potential difficulty, she said, is using the model to test the efficacy of a vaccine given soon after exposure in preventing a small number of viruses from replicating toward a full-blown infection. “If the number of viruses gets too large in the short time you have from getting the vaccine and making the antibodies, you can’t cope with the quantity,” she said. “Once the individual is really sick, it’s too late.” Jahrling acknowledged that weakness in the current model, but said it would nevertheless be useful in testing the vaccine as a preventive measure — administered before exposure, he said. “For that, this animal model is just fine.” Jahrling also stressed the primate model’s utility in treating the virus with drugs. “The important thing is to get a systemic infection that you can then demonstrate treatment efficacy against. I can point out a lot of animal model systems that are not very faithful to the human disease,” he said. Some Opposition Some critics suspect the army simply wants to keep the smallpox around indefinitely, and the military’s research is part of an attempt to do that, Jahrling said. Taking it one step further, a Jan. 12 article by an Indian official in the British Medical Journal made the unsupported claim the United States intends to develop new offensive biological weapons, which were officially abandoned when the United States signed the 1972 Biological Weapons Convention. Kalyan Banerjee, a member of the WHO's ad hoc committee on orthopoxviruses who dissented on the WHO’s recent recommendation to retain smallpox stocks, charged it would be used by the U.S. military to develop smallpox as a weapon. Jahrling said the criticism is “completely unjustified.” His research, he said, could be used instead to eventually eliminate the need for using smallpox in vaccine testing. “What I’m frankly hoping is over time we can develop enough parallels and bridges over smallpox in monkeys and monkeypox in monkeys that the Food and Drug Administration will accept monkeypox in monkeys as a surrogate and we can get out of the smallpox business,” he said.
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