Conformationally-Constrained PA Anthrax Vaccine

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DESCRIPTION (provided by applicant): Bacillus anthracis, the agent that causes anthrax, has several characteristics that make it a formidable bioterrorist threat. Presently efforts to develop an effective anthrax vaccine can be categorized into the following groups: (1) Protein vaccines; (2) Live attenuated vaccines; (3) DNA and replicon vaccines: and (4) Identification of new antigens. The steps in host-cell intoxication have been recently clarified. An 83-kDa form of protective antigen (PA83) is secreted from rapidly growing B. Anthracis cells and binds via a 19aa solvent-exposed loop in domain 4 between strand 4A-4B of the protective antigen (PA) to a specific host cell surface receptor termed ATR. X-ray crystallography studies characterized this loop as having the structure of the complementarity-determining region (CDR) of an immunoglobulin (Ig). It is the goal of this application to develop and test as a proof-of-principle a series of Ig molecules expressing a conformationally-constrained 4B9-4B10 PA loop, antigenized antibodies. Furthermore, we will ascertain whether immunization with antibodies antigenized to express 4B9-4B 10 PA loop will result in the induction of site specific antibodies (i.e., directed at the 4B9-4B 10 PA loop) also able to neutralize the internalization of B. anthracis toxin and its cytopathicity. It is hoped that the idea and experiments proposed in this application can speed up the development of a safe and effective method to vaccinate against B. anthracis.