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MICROBIOLOGY Dual Action Anthrax Vaccine Tops Current Vaccine in Early Tests Approach May Also Act as Therapy to Help Those Infected Keep Bacteria in Check Researchers at HMS and Brigham and Women's Hospital have created a vaccine that delivers a one-two punch to anthrax and could become a powerful defensive weapon against bioterrorism. Julia Wang (left), Gi-Eun Rhie, and colleagues developed a dually active anthrax vaccine that promises both better protection against anthrax infection and more effective treatment for people already infected. (Photos by Phil Farnsworth) The new vaccine prods the immune system to attack both the anthrax bacterium (Bacillus anthracis) and the toxins it makes. This dual action represents an improvement over the currently available vaccine, which targets only the toxins. In a test of the vaccine using mice, animals were injected first with the vaccine, then 10 days later with anthrax toxin. All the vaccinated mice survived though unvaccinated mice exposed to the toxin died within 24 hours. "Clearly, there is a need for a better anthrax vaccine. The bivalent vaccine we came up with is likely to be much more effective at protecting against systemic anthrax because it targets both virulence factors of Bacillus anthracis--its toxin and its capsule." --Julia Wang "It worked like a charm," said Julia Wang, HMS assistant professor of medicine (microbiology and molecular genetics) at Channing Laboratory and BWH, who led the study. "Clearly, there is a need for a better anthrax vaccine. The bivalent vaccine we came up with is likely to be much more effective at protecting against systemic anthrax because it targets both virulence factors of Bacillus anthracis--its toxin and its capsule." The researchers, including first author Gi-Eun Rhie, HMS research fellow in microbiology and molecular genetics, say that the new vaccine may also be a therapeutic tool for treating those already infected with anthrax. Research suggests that it may be important to raise antibacterial antibodies in those individuals to combat bacilli that multiply in victims long after antibiotic treatment has ended. Double Whammy To make the vaccine, the scientists chemically joined two anthrax molecules that are the bacterium's major virulence factors in disease, but act as antigens in a vaccine, stimulating the host's immune system to produce antibodies. One is protective antigen, a protein that joins with another called lethal factor to make the anthrax lethal toxin that kills immune cells. This combined protective antigen, made by genetically modified E. coli bacteria, is the basis of the existing anthrax vaccine and was also used in the experimental version. In addition to protective antigen, the new vaccine incorporates capsular poly-gamma-D-glutamic acid (PGA), a polypeptide making up the capsule that hides the bacterium from immune attack, allowing it to replicate unchallenged. PGA normally elicits a weak immune response, but when coupled with the highly immunogenic protective antigen, it becomes strongly immunogenic itself. Using a harmless bug, Bacillus licheniformis, which has a capsule identical to that of anthrax, the researchers purified PGA for use in the vaccine. Next, they injected mice with the vaccine three times over four weeks and drew the animals' blood to measure immunoglobulins specific to the protective antigen and PGA. They found that levels of PGA- and protective antigen-specific immunoglobulin G each rose significantly after the three injections. Using immunoelectron microscopy, the investigators showed that the PGA antibodies surrounded the capsule of B. licheniformis, standing in for B. anthracis, and successfully recruited lethal complement proteins. Likewise, the scientists showed that mouse blood containing antibodies to protective antigen protected cells against damage from anthrax toxin by blocking protective antigen. The findings appear in the Proceedings of the National Academy of Sciences online early edition for the week of Sept. 1 and will be published in the Sept. 16 print edition. "This study provides a good example of how scientists not previously trained in biodefense research can quickly make a contribution once they put their heads together on a problem," said co-author John Mekalanos, head of the Department of Microbiology and Molecular Genetics at HMS. The authors further suggest that the dual action approach might be used in vaccines against other microorganisms. Wang said the vaccine will now have to be tested in animals infected with actual anthrax spores--as opposed to the recombinant lethal toxin used in this study--to replicate the natural disease process. Additional authors on the study are John Collier, the Maude and Lillian Presley professor of microbiology and molecular genetics at HMS; HMS research assistant Michael Roehrl; and HMS research fellow Michael Mourez. --Tom Reynolds