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Epitope Bias Found in Bacillus Anthracis Protective Antigen
| "We're the first group that has tried to look at the whole assortment of antibodies, and that was the first step in uncovering the epitope bias." |
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."
| "If this epitope domain is no longer involved in the intoxication process and most of the body's antibodies are binding to it, they're binding to a location where they can't actually give rise to toxin neutralization." |
This could explain why the currently licensed vaccine is not as immunogenic as scientists would like.
"The vaccine series takes 3 injections 2 weeks apart and then 3 more injections 6 months apart, for a total of 6 injections over 18 months," Dr. Reason says, "and that's before you're fully protected. You also need an annual booster to maintain antibodies." Which is the reason a next generation vaccine for anthrax has been under development - but the problem is that both the current vaccine and those under development utilized the same form of PA. As a result, Dr. Reason and his colleagues are suggesting a rethink. "What we're proposing is that this may be a time to stop and see if the PA molecule can be modified to shift the dominant epitope domain away from this terminal one," says Dr. Reason. While the current analysis was conducted on the antibody response of only a single individual, Dr. Reason and his colleagues expect to find similar results in an upcoming study to be published within the next 6 to 10 months based on analyses of multiple individuals. |
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.
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