Unique Neisseria Meningitidis B Capsular Epitopes

描述（由申请人提供）：脑膜炎奈瑟菌B群荚膜多糖（MBPS）是α (2-8) n -乙酰神经氨酸的聚合物，化学上与自身抗原聚唾液酸（PSA）相同。用丙酰取代n -乙酰基（N-Pr - MBPS）的MBPS蛋白结合疫苗免疫小鼠，可产生一种具有杀菌作用但不与人PSA交叉反应的血清抗体亚群。我们已经鉴定出在合成N-Pr MBPS过程中产生的去n -乙酰化MBPS衍生物，这些衍生物也存在于B群细菌的胶囊中，并且是抗N-Pr MBPS抗菌单克隆抗体（mAb）的靶标，该抗体不与人PSA抗原交叉反应。本提案的目标是：1)开发新的化学和生物合成方法来制备去n-乙酰基MBPS衍生物，用于确定其他非自反应性抗菌抗囊单抗识别的表位结构，并用于制备MBPS原型疫苗。我们的假设是，由同一疫苗引发的其他保护性、非自身反应性单克隆抗体也能识别含有去n-乙酰基残基的MBPS衍生物，并且NmB细菌自然表达相同或类似的MBPS表位。2)确定B族细菌自然表达的荚膜PS表位的结构，这些表位可以被非自反应性杀菌单抗识别。我们的假设是，非自反应性抗包膜单抗识别的B族包膜表位与N-Pr MBPS化学合成过程中产生的MBPS衍生物相似或模仿，并且很少存在于宿主组织中。3)基于MBPS衍生物和B族胶囊中独特的荚膜表位，开发B族疫苗。我们的假设是，确定的表位可以用来设计抗原，引发杀菌，非自身反应性抗体。因此，该建议提供了一种新的方法来开发保护性的基于ps的疫苗，避免了引发自身抗体的安全问题，并了解B组荚膜和宿主PSA抗原之间的结构差异。

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 Immunization of mice with a MBPS-protein conjugate vaccine in which N-acetyl groups have been replaced by propionyl groups (N-Pr MBPS) elicits a subpopulation of serum antibodies that are bactericidal but do not cross-react with human PSA.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.