Unique Neisseria Meningitidis B Capsular Epitopes

描述(申请人提供)：脑膜炎奈瑟氏菌B组胶囊多糖(MBPS)是α(2-8)N-乙酰神经氨酸的聚合物，在化学上与自身抗原聚唾液酸(PSA)相同。用N-乙酰基被丙酰基(N-Pr Mbps)取代的Mbps蛋白结合疫苗免疫小鼠，产生一种具有杀菌作用但不与人PSA发生交叉反应的血清抗体亚群。我们已经鉴定了在合成N-Pr Mbps的过程中产生的Mbps的去N-乙酰化衍生物，这些衍生物也在B组细菌的胶囊中，并且是一种杀菌的抗N-Pr Mbps单抗(MAb)的靶标，该单抗不与人PSA抗原发生交叉反应。这项建议的目标是：1)开发新的化学和生物合成方法来制备去N-乙酰Mbps衍生物，用于确定其他非自身反应性杀菌抗囊单抗识别的表位的结构，并用于制备Mbps疫苗原型。我们的假设是，由同一疫苗诱导的其他保护性、非自身反应性单抗也识别含有去N-乙酰基残基的Mbps衍生物，而NMB细菌自然表达相同或相似的Mbps表位。2)确定非自身反应性杀菌单抗识别的B组细菌自然表达的包膜PS表位的结构。我们的假设是，非自身反应性抗囊单抗识别的B组囊膜表位类似于或被N-Pr Mbps化学合成过程中产生的Mbps衍生物所模仿，在宿主组织中很少存在。3)基于在MBPS衍生物和B群胶囊中确定的独特的囊膜表位，开发B群疫苗。我们的假设是，所识别的表位可用于设计抗原，以诱导杀菌、非自身反应抗体。因此，这一建议提供了一种新的方法来开发保护性的PS疫苗，避免了引发自身抗体的安全问题，并为了解B组被膜和宿主PSA抗原之间的结构差异提供了一种新的方法。

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 Immunization of mice with a MBPS-protein conjugate vaccine in which N-acetyl groups have been replaced by propionyl groups (N-Pr MBPS) elicits a subpopulation of serum antibodies that are bactericidal but do not cross-react with human PSA.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