Research team developing new defenses against plague and smallpox

Using a federal biodefense grant, a Wake Forest University Baptist Medical Center team will try to develop new approaches to immunizing people against the plague and smallpox, two of the most feared potential agents of bio-terrorism.

“Our efforts might ultimately lead to the development of vaccines that can be used to protect Americans against these pathogens,” said Steven B. Mizel, Ph.D., principal investigator.

Mizel discovered. that a bacterial cell protein can greatly enhance the effectiveness of vaccines. The protein, called flagellin, is taken from bacterial flagella, whiplike appendages that are used by bacteria to move around their environment.

“We have shown that flagellin is extraordinarily effective in punching up the immune system,” said Mizel, professor and chairman of the Department of Microbiology and Immunology. “Flagellin is an adjuvant, and adjuvants increase the efficacy of vaccines.”

Injecting a protein taken from plague bacteria into a mouse – one method of vaccination-- produces a response from the mouse immune system, but it is almost undetectable. “If you mix flagellin with that protein and inject it into the mouse, you get antibody levels that are 500,000 times higher,” Mizel said. “This is extraordinary and opens the door to the use of flagellin as an adjuvant in humans.”

The next step is testing the approach in monkeys, which will begin in the fall, as part of the $9.125 million five-year research program funded by the National Institutes of Health.

Mizel’s project is just one aspect of the research program, which involves six other medical school scientists and a secure biosafety laboratory at Virginia Tech that is certified by the Centers for Disease Control and Prevention and the FBI to work with dangerous pathogens. Mizel said the actual challenges of vaccines with plague and smallpox will occur in that safe laboratory and not on the Wake Forest Baptist campus.

Two projects will test using viral vaccine vectors – viruses that don’t cause disease – as ways to carry into the body proteins for the plague or pox viruses and “hopefully improve the immune response,” Mizel said.

Griffith D. Parks, Ph.D., associate professor of microbiology and immunology, will be testing a monkey virus known as SV5, and Douglas S. Lyles, Ph.D., professor and chairman of the Department of Biochemistry, will be testing variants of a virus called VSV (vesicular stomatitis virus).

“Not only are these novel vaccine vectors, but we’re going to make viruses that encode flagellin so they’ll get the extra bang of having flagellin there.” Mizel said.

In the fourth project, Martha Alexander-Miller. Ph.D., associate professor of microbiology and immunology, will be exploring the mechanism by which viruses like smallpox suppress the immune response, and thereby successfully invade the body. Mizel said Alexander-Miller has already found that pox viruses suppress the respiratory response in the lungs.

Mizel sees the work going well beyond plague and smallpox to developing methods to rapidly produce vaccines for many diseases. “We’re confronted every day with newly emerging disease-causing organisms – SARS, West Nile virus, Ebola virus, HIV-AIDS. The key is to establish better methods to immunize people.

“It is very clear that the age of antibiotics is over. Drug resistance has become a serious problem so we have to return to developing better vaccines,” Mizel said.

The research team also includes Jason Grayson, Ph.D, and Beth Hiltbold, Ph.D., both assistant professors, and Nancy Kock, D.V.M., Ph.D., a veterinary pathologist..