Sep. 2, 2003 BOSTON, MA –- Researchers at Harvard Medical School 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.
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 the toxic challenge, while unvaccinated mice exposed to the toxin died within 24 hours.
"It worked like a charm," said Julia Wang, Harvard Medical School assistant professor at Brigham and Women's Hospital, who led the study. "Clearly, there is a need for a better anthrax vaccine," she added. "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 suggest that the new vaccine will also be an important tool for treating those already infected with anthrax as a so-called therapeutic vaccine. Research shows it may be important to raise antibacterial antibodies in those individuals to combat bacilli that multiply in victims long after antibiotic treatment has ended.
To make the vaccine, the scientists chemically joined two anthrax molecules that are the bacterium's major virulence factors in disease, but in a vaccine act as antigens, stimulating an infected person's immune system to produce disease-fighting 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 vaccine.
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 the host's immune system, allowing it to replicate unchallenged. PGA normally elicits only a weak immune response, but when coupled with the highly immunogenic protective antigen, it becomes strongly immunogenic itself. Taking advantage of a harmless bacterium, Bacillus licheniformis, which has a PGA capsule identical to that of anthrax, the researchers purified PGA from B. licheniformis for use in the vaccine.
Next, they injected mice with the vaccine three times over four weeks and drew the animals' blood to measure antibodies (immunoglobulins) specific to the protective antigen and PGA antigens. 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 (again serving as a stand-in for B. anthracis). The antibodies successfully recruited complement, a part of the immune system that kills microorganisms by disrupting their cell membranes. 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.
"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 Harvard Medical School. 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 sporesæas opposed to the recombinant lethal toxin used in this study to replicate the natural disease process.
The lead author on the study is HMS research fellow Gi-Eun Rhie. Additional authors are HMS professor John Collier, HMS research assistant Micheal Roehrl, and HMS research fellow Micheal Mourez.
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