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April 15, 2002

VRC joins war against anthrax, bioterrorism

By Poul Olson


The Vaccine Research Center has begun a five-year study of Anthrax Vaccine Adsorbed (AVA), the only human vaccine approved for the bacterium, Bacillus anthracis.

Sponsored by a $4.2 million grant from the Centers for Disease Control and Prevention (CDC) and under the direction of Robert Mittler, assistant professor of surgery and a VRC researcher, the program will assess and compare the efficacy of three different vaccine regimens in rhesus macaque monkeys starting in June. Research-ers also hope to determine the strength of protective immunity against anthrax after inoculation.

No live anthrax bacteria will be used in theYerkes study; Mittler and his team instead will use harmless proteins derived from anthrax toxins to assess the immune response promoted by AVA.

The study will involve 33 rhesus macaques equally divided among three groups. One group will receive a course of three AVA shots at full concentration. A second group will be vaccinated with three shots diluted to 10 percent strength, and the third group of monkeys will be inoculated with three shots at 5 percent of the full concentration. A single monkey in each group will serve as a control and will receive a placebo shot.

When inhaled, anthrax spores enter specialized immune cells called macrophages, where they germinate into vegetative cells that produce two deadly toxins that kill cells. Death can result as quickly as two days after these toxins enter the circulatory system. AVA produces antibodies against a component of the toxin called protective antigen (PA). By blocking the activity of PA, these antibodies prevent the toxins from entering and subsequently killing cells.

Since 1970, when the U.S. Food and Drug Administration licensed AVA for human use, more than 2 million doses of the vaccine have been administered, mostly to members of the military. Like most vaccines, AVA has side effects, including redness and swelling at the injection site.

Concerns that it also may have more serious systemic effects, however, were raised in the mid-1990s after a number of Gulf War veterans who received AVA began experiencing an unusual variety of neurological disorders that came to be called Gulf War Syndrome. Pressure to study this unusual malady prompted Congress to mandate new research on AVA. The CDC’s AVA research program emerged from this initiative.

Although a number of new anthrax vaccines are under development, BioPort Corp. of Lansing, Mich., is the nation’s sole producer of anthrax vaccine.

Mittler described the manufacturing process for AVA as “crude,” based on modern standards of vaccine production. Bacillus anthracis are grown in large fermentation vats, then filtered out, leaving behind an anthrax-free broth of proteins produced by the bacteria. These proteins are subsequently used to immunize human recipients.

The threat of anthrax as a bioterrorism agent became a public reality last fall following a series of mailings of anthrax spores and the deaths of five people. In the wake of these attacks, federal funding for research on anthrax, smallpox, and other potential bioterrorism agents has increased substantially.

AVA has drawn criticism for the large number of shots associated with the vaccine regimen and the amount of time needed to raise protective immunity. No other human vaccine requires as many shots as AVA, noted Mittler.

sWith the resurgence of government interest and funding for anthrax research, BioPort may soon face some competition. “The technology exists today,” Mittler said, “to clone those specific proteins that produce the anthrax toxins and thus develop a much more refined and targeted anthrax vaccine.”

Mittler’s co-investigators at VRC are researcher Chris Ibegbu, VRC Director Rafi Ahmed and veterinarian Denyse Levesque.