New combination vaccine effective against plague

Plague, a bacterium that ravaged Europe in the Middle Ages and is today one of the most feared potential agents of bio-terrorism, may have met its match, according to Wake Forest University School of Medicine scientists.

Steven B. Mizel, Ph.D., principal investigator, told the American Gastroenterological Association meeting in Chicago that when mice immunized with a new combination vaccine were challenged with a lethal dose of Yersinia pestis, the bacterium that causes plague, “the immune mice survived but the control mice succumbed in three days.”

Mizel and his graduate student, Anna Honko, found that injecting a protein taken from plague bacteria into a mouse – one method of vaccination – produces little if any response in the mouse immune system. But if a protein termed flagellin is added to the vaccine, antibody levels against the plague bacteria are 500,000 times higher.

“Flagellin can function as an effective adjuvant, making a vaccine that protects against the most dangerous form of the plague – pneumonic plague,” reported Mizel, professor and chairman of the Department of Microbiology and Immunology at the School of Medicine, part of Wake Forest University Baptist Medical Center in Winston-Salem.

Pneumonic plague occurs when an individual breathes in plague bacteria. Untreated, the victim dies within three to four days.

“We have also established that flagellin is an effective adjuvant in monkeys immunized with flagellin and a Yersina pestis antigen,” he said. “The immunized monkeys showed no undesired effects from the vaccine. There was no fever or other signs of problems.

“These results clearly establish a strong foundation for the future use of flagellin as an adjuvant in humans,” Mizel said.

He said the research shows that the mice were protected for at least three months after immunization.

The work is part of a $9.125 million, five-year research program funded by the National Institutes of Health under a federal bioterrorism initiative. “The development of a vaccine against the pneumonic or respiratory form of plague is a major goal of the bio-defense initiative,” he said.

The research program 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 against plague are occurring in that safe laboratory in Blacksburg, Va., and not in Winston-Salem.

Flagellin is taken from bacterial flagella, whiplike appendages that are used by bacteria to move around their environment. Thus it is possible for animals that have been exposed to a different bacterial infection to have antibodies against flagellin. But Mizel and his colleagues found that flagellin is equally effective in animals with such antibodies as it is in mice that had never encountered flagellin before.

“Prior immunity to flagellin does not impair its ability to function as an adjuvant,” Mizel said. “This means that flagellin can be used multiple times with different types of vaccines. The new plague vaccine also has the advantage of not requiring a needle since only a few drops in the nose provide protection.”

In view of the exciting results with the plague vaccine, Mizel plans to determine if immunized monkeys are protected against the plague. If they are then efforts will be initiated to begin studies in humans.