The Key to Unlocking to A Better Vaccine
Epitope Bias Found in Bacillus Anthracis Protective Antigen
In a new study just published in Molecular Immunology, CHORI scientist Donald C. Reason, PhD, and his colleagues utilized repertoire cloning to discover a significant weakness in the Bacillus anthracis protective antigen (PA), the primary immunogenic component found in both the currently licensed anthrax vaccines as well as new vaccines under development.
“This is first ever study, to my knowledge, to reveal the epitope bias,” says Dr. Reason. “It’s difficult to do because you have to clone a significant number of antibodies.”The key to identifying the epitope bias was in Dr. Reason's techniques. "When you're infected or vaccinated, the response is actually a complex of many different individual antibodies," Dr. Reason explains. "With repertoire cloning, we're able to clone and isolate many, if not all, of the antibodies that make up that response."
As a result, Dr. Reason and his colleagues can analyze all the clonal members of a given antibody response one by one, and identify the epitopes, or locations, on the PA they bind.
"What we've done so far is a kind of broad sweep, not looking at the exact epitope, but the general region of the molecule, or epitope domain, where the different antibodies bind," says Dr. Reason.
Normally, when PA functions as a toxin in an infected individual, it binds to the cell surface and serves as the recognition unit that allows other toxins to enter the cell. While the form of PA in the vaccine is not toxic, it still causes the body to make antibodies that will also recognize toxic PA and prevent a full blown anthrax infection from occurring.
"What we found in this study is that there is a particular region of the molecule that the majority of the antibodies bind to," Dr. Reason says. "We think this is significant because that region of the molecule is cleaved from the remainder of the PA very early in the intoxication process and has no role in intoxication."
This epitope bias could result in a significantly weaker immune response than might otherwise be achieved. As Dr. Reason explains "It's almost like a decoy."
Such results would confirm whether this study represents a unique or general phenomenon. In the mean time, however, Dr. Reason and his colleagues are already teasing out some theories as to why the epitope bias takes place, and how it can be modified as a result.
"We're looking at ways to do minimal manipulation of the PA molecule so that it gives rise to a better antibody response by eliminating the epitope bias," says Dr. Reason. "At the same time, we want to maintain its ability to induce the protective antibodies."
If their current research is any indication, Dr. Reason and his colleagues will no doubt be able overcome the epitope bias they discovered, and in so doing, take us yet another step toward a better and more protective anthrax vaccine.Back
Monday, May 16, 2011 11:33 PM