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Smallpox I: U.S. Official Questions New Army Test Model By David Ruppe U.S. Army scientist last year managed to fatally infect a primate with the smallpox virus, holding out the promise of a much-needed animal host for testing new vaccines and anti-viral drugs. The lack of such a host, experts said, has been a roadblock to testing and ultimate federal approval of newer, safer vaccines and treatment drugs for humans. But the monkey model — cynomolgus macaques injected with unusually high concentrations of the variola virus — may not be suitable for testing vaccines and imperfect for testing drugs, D.A. Henderson, director of the Health and Human Services Department’s Office of Public Health Preparedness, told Global Security Newswire yesterday. “I think what he’s saying is that he has made a stride forward in demonstrating that you can infect a monkey, but, now, the utility of the model is another question,” said Henderson, referring to U.S. Army Medical Research Institute of Infectious Diseases scientist Peter Jahrling, who described the development to GSN story last week (see GSN, Jan. 24). Still, Henderson, who prior to joining the administration last fall, openly advocated ending such testing and destroying the world’s remaining stocks of the virus, called the new model “an advance” that “could be useful” and said further work with the model is warranted. While Henderson does not have a role in the Federal Drug Administration decision to approve the monkey model, his views carry a lot of weight in the scientific community and the administration, said Jahrling. “He’s a pretty powerful guy. He’s got a $3 billion checkbook to play with.” Questions About Testing Vaccines Citing the way the monkeys were infected, Henderson expressed doubt the model could be used for testing new vaccines. “If you were going to test for a vaccine, you are obviously looking for a level of protection for an individual who would be getting it by inhalation,“ said Henderson. As the model involves injecting the disease, he said, “this really wouldn’t have a lot of relevance, I don’t see how this would have relevance to testing a vaccine.” Henderson also questioned whether the unnaturally high concentration of the virus injected into the monkeys, needed to give them the infection, would provide a realistic model for testing. “You face the problem of presenting an overwhelming kind of infection and one has to ask the question, ‘would this be like the infection that an individual would experience under normal circumstances?’” he said. Counterpoints Jahrling has challenged such criticism, arguing the important thing is to be able to create a systemic infection in the model. Also providing counterarguments is Harry Keyserling, an Emory University infectious disease expert who said he is not directly familiar with the Army research. He said using an animal model using injections, rather than aerosolized transmission, is not necessarily a problem for testing vaccines and treatment. “The natural route is of course through inhalation or skin contact,” Keyserling said. “But with a direct inoculation model, you would still be able to determine the effectiveness of drugs … So this is not an unusual way to study a pathogen.” Subjecting the animal to a high concentration may not necessarily be a disadvantage either depending upon the objective, he said. “The same thing could be said in humans, that any inoculum could overwhelm vaccine protection. So there’s always a balance between immune response and the amount of pathogen you deliver.” With respect to chemotherapy, he said, there are ways of monitoring the effects of anti-viral drugs that would be less of a problem with a large inoculum. “The drug either has some effect, or no effect, and you can quantify the magnitude of the effect,” Keyserling said. The only vaccine currently approved by the FDA, Dryvax, was tested in the field during the successful global campaign led by Henderson to rid the world of the disease in the 1960s and 1970s. But the vaccine had significant side effects, particularly in people with weakened immune systems. Testing of the live virus cannot be done on humans, for obvious reasons, and the only other animal until now that could be fatally infected, according to Henderson, was the chimpanzee, the closest living animal relation to humans — an unsuitable option because they are disappearing from the wild. “We’ve got very, very few of them. And to use them in work on a disease that could be fatal in a fair proportion I think is just not on,” said Henderson. Questions About Testing Anti-Viral Drugs In addition to vaccine research, the monkeys may also be useful in developing smallpox treatment drugs, Jahrling said. There currently are no anti-viral agents proven effective in treating smallpox after the disease is diagnosed, though there are some under development. Henderson also questioned the model’s usefulness in testing such drugs, observing that Jahrling’s testing data showed most of the monkeys died fairly rapidly without developing much of a rash, an important sign cuing doctors to identify smallpox. Two of Jahrling’s 16 test monkeys lived longer than the others and did develop significant rashes. “Now, if we’re looking for a drug to treat smallpox … then one would want to know if the drug has an effect on the disease after the patient is identified as having the disease,” he said. In its current form, said Henderson, “as I’m sure Dr. Jahrling himself would say, this is certainly not ready for prime time ... ” Plan for the Future Jahrling is hoping to do more testing of the model using a slightly reduced concentration of the virus, so the animals would die more slowly, mirroring the likely human progression. “It may be flawed, but it’s infinitely better than nothing and we do have plan to refine it and make it better,” he said. He also is planning to soon submit a paper to Science magazine for peer-reviewed publication, which might give the research a strong endorsement.
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