Unique Neisseria Meningitidis B Capsular Epitopes

Children'S Hospital & Res Ctr At Oakland, Oakland CA

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Abstract

DESCRIPTION (provided by applicant): The Neisseria meningitidis group B capsular polysaccharide (MBPS) is a polymer of alpha(2-8) N-acetyl neuraminic acid and is chemically identical to an autoantigen, polysialic acid (PSA). Immunization of mice with a MBPS-protein conjugate vaccine in which N-acetyl groups have been replaced by propionyl groups (N-Pr MBPS) elicits a subpopulation of serum antibodies that are bactericidal but do not cross-react with human PSA. We have identified de-N-acetylated derivatives of MBPS that are produced during the synthesis of N-Pr MBPS that are also in the capsule of group B bacteria and are the target of a bactericidal anti-N-Pr MBPS monoclonal antibody (mAb) that does not cross-react with human PSA antigens. The goals of this proposal are: 1) Develop novel chemical and biosynthetic methods for preparing de-N-acetyl MBPS derivatives for use in determining the structure of epitopes recognized by other non-auto-reactive bactericidal anticapsular mAbs and for preparing prototype MBPS vaccines. Our hypothesis is that other protective, non- autoreactive mAbs elicited by the same vaccine also recognize MBPS derivatives containing de-N-acetyl residues and that NmB bacteria naturally express the same or similar MBPS epitopes. 2) Determine the structure of capsular PS epitopes expressed naturally by group B bacteria that are recognized by non- autoreactive, bactericidal mAbs. Our hypothesis is that group B capsular epitopes recognized by non- autoreactive anticapsular mAbs are similar to or are mimicked by MBPS derivatives produced during the chemical synthesis of N-Pr MBPS and are present rarely, if at all in host tissues. 3) Develop a group B vaccine based on the unique capsular epitopes identified in MBPS derivatives and the group B capsule. Our hypothesis is that the epitopes identified can be used to design antigens that elicit bactericidal, non- autoreactive antibodies. Thus, this proposal offers a novel approach to develop a protective PS-based vaccine that avoids safety concerns of eliciting autoantibodies and for understanding structural differences between group B capsular and host PSA antigens.