Terrorists who scheme to weaponize smallpox as a disease of mass destruction may find their project more fraught than a stroll in the park - but far from impossible.

"The threat of smallpox persists because clandestine stockpiles of variola virus still exist," observed immunologist Ariella Rosengard, at the University of Pennsylvania in Philadelphia. She bases her evidence for this surmise on the historical fact that smallpox was eradicated worldwide in 1978 by the World Health Organization's Donald Henderson.

"It is obviously something the U.S. is nervous about," Rosengard pointed out, "which is why they are increasing funding for research on something that's already been eradicated. We want to keep it eradicated," she added, "and the best way is to let the world know that we actually have a treatment. That would really disarm terrorists who have any thoughts about doing something nefarious with variola virus.

"However," she said, "you can't predict the mind of a madman. He can think up horrible thoughts that we can't even imagine. So the best defense against any virus is to have a safe therapy and vaccine."

Rosengard is lead author of a paper in the Proceedings of the National Academy of Sciences (PNAS) dated May 28, 2002. It bears the title: "Variola virus immune evasion design: Expression of a highly efficient inhibitor of human complement."

"There are three different ways to consider our findings," she told BioWorld Today. "One way is to look at the research. For a long time we were unable to study variola, because the virus and its viral DNA and proteins were not available to us. What I showed is that we can learn a lot about the virus if we molecularly engineer the proteins from one of variola's close orthopox virus cousins, such as vaccinia virus. That is an important finding because until now, since variola's eradication, research could only be performed in two places that we knew of - one in the Russian laboratories and one in the CDC," the Centers for Disease Control and Prevention in Atlanta.

Variola Out Of Bounds To Investigators

"The U.S. is a big country," Rosengard continued, "and we have a lot of excellent scientists who are not necessarily working at those two centers. Their only way to truly create roadblocks for the smallpox virus is to have more people trying to understand it. Our paper describes a way to do this safely. It provides many of us in the virology world and the immunology world an approach to studying this virus. Before, I think people just put their hands up and said, Well, it would be great, but I can't get ahold of variola, so I can't study it.' It was wonderful when it was eradicated. We thought all our problems were over. I think 9/11 made us realize that maybe we shouldn't be as comfortable as we would like to be.

"Another implication," Rosengard went on, "is that for years virologists would say [that] variola virus was able to infect only humans - because it could. And most probably it could because it was better able to overcome human immunity. Smallpox is caused by variola virus, which is a member of the orthopox viral family," she pointed out. "Its exclusive reservoir is the human body, which is why it could be eradicated in the first place. Imagine if it had infected rodents or mosquitoes, too. It would have been impossible to eradicate it. But we knew it was spread from human to human, and there was no other reservoir. Smallpox wiped out whole communities in the centuries when it was endemic."

In its war against the human race, variola zeroes in on two weapons deployed by the human immune defenses - innate immunity and the complement system. Between them, these two arms operate like a SWAT team.

"Human complement is part of the innate immune response," Rosengard explained. "It goes into action immediately when a virus, bacterium, fungus or other pathogen enters the body. We reverse-engineered a variola protein from vaccinia, a related virus formerly used to vaccinate against smallpox. We named this protein the Smallpox Inhibitor of Complement Enzymes' - SPICE for short. SPICE presumably helps variola virus elude complement. It does not cause or spread smallpox itself.

"SPICE is only one of several hundred proteins that contribute to the virus' pathogenesis and human host species preference. To understand its role, we compared the activity of SPICE to that of human complement regulatory proteins and vaccinia's complement control protein. Variola, we found, has its own species-specific human complement regulatory proteins. If the virus is able to inactivate the complement by producing a protein like SPICE, then our first line of defense is to defeat it. So wouldn't it be good from a biotech point of view," she asked rhetorically, "to disable SPICE, to allow our innate immune response to function? Our findings showed that SPICE is an important molecule that the virus produces, which is capable of overcoming and inhibiting human complement.

"Our approach," Rosengard noted, "enabled us to study variola without the risks of using the entire virus. We do so to make the smallpox less virulent and our future smallpox vaccine safer. Achieving these goals would be the most effective way to disarm bioterrorists."

Vaccination Packed Its Own Caveats

"The original smallpox vaccine was not entirely without risk," she recalled. "In those days they were able to avoid vaccinating women who were pregnant, people who were immunosuppressed, or children with eczema, and even avoid household or occupational contact with these people."

Rosengard said, "Nowadays we have many more immunosupressed patients than 30 or 40 years ago. We didn't have the AIDS epidemic, and cancer patients died more quickly. We're now able to keep patients alive with chemotherapy. But they are the patients we dare not be around when we vaccinate people in the future.

"Imagine there's an outbreak, and the U.S. decides to vaccinate the entire population. We would have to ask people we work with: Oh by the way, I'm going to be vaccinated. Are you immunosuppressed for any reason?'"

The university applied in 1998 to patent one of two SPICE inventions, with Rosengard as sole inventor.

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