Unique Neisseria Meningitidis B Capsular Epitopes

独特的脑膜炎奈瑟菌 B 荚膜表位

• 批准号: 7418986
• 负责人: GREGORY R MOE
• 金额: $ 60.29万
• 依托单位: CHILDREN'S HOSPITAL & RES CTR AT OAKLAND
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-05-15 至 2010-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7418986
• 关键词: Acids; Address; Amines; Anabolism; Antibodies; Antigenic Specificity; Antigens; Autoantibodies; Bacteremia; Bacteria; Binding; Cavia; Chemicals; Complement; Conjugate Vaccines; Deposition; Development; Disease; Encapsulated; Enzyme-Linked Immunosorbent Assay; Epitopes; Flow Cytometry; Goals; Group Structure; Human; Human Cell Line; Immune Sera; Immunization; Infant; Investigation; Life; Manufacturer Name; Mass Spectrum Analysis; Measures; Mediating; Methods; Microbiology; Modeling; Monoclonal Antibodies; Mus; NMR Spectroscopy; Neisseria meningitidis; Neuraminic Acids; Organic solvent product; Organism; Pathogenesis; Polymers; Polysaccharides; Polysialic Acid; Prevention; Proteins; Rattus; Risk; Role; Safety; Serum; Sialic Acids; Structure; Surface; Testing; Tissues; To autoantigen; Today; Vaccines; bactericide; base; capsule; chemical synthesis; design; disorder prevention; immunogenicity; meningococcal group B polysaccharide; microcalorimetry; mutant; novel; novel strategies; pathogen; prototype

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 Immunization of mice with a MBPS-protein conjugate vaccine in which N-acetyl groups have been replaced by propionyl groups (N-Pr MBPS) elicits a subpopulation of serum antibodies that are bactericidal but do not cross-react with human PSA.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

描述（由申请人提供）：B组脑膜炎奈瑟菌荚膜多糖（MBPS）是α（2-8）N-乙酰基神经氨酸的聚合物，并且在化学上与自身抗原聚唾液酸（PSA）相同。用MBPS-蛋白结合疫苗（其中N-乙酰基已被丙酰基取代）（N-Pr MBPS）对小鼠进行免疫接种，可引发血清抗体亚群，这些抗体具有杀菌作用，但不与人PSA发生交叉反应。我们已经鉴定出 MBPS 的脱 N-乙酰化衍生物，这些衍生物是在 N-Pr MBPS 合成过程中产生的，它们也存在于 B 组细菌的荚膜中，并且是杀菌性抗 N-Pr MBPS 单克隆抗体 (mAb) 的目标不与人类 PSA 抗原发生交叉反应。该提案的目标是： 1) 开发新的化学和生物合成方法，用于制备脱 N-乙酰基 MBPS 衍生物，用于确定其他非自身反应性杀菌抗荚膜单克隆抗体识别的表位结构，并用于制备原型 MBPS 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识别含有脱N-乙酰基残基的MBPS衍生物，并且NmB细菌自然表达相同或相似的MBPS表位。 2) 确定 B 组细菌自然表达的荚膜 PS 表位的结构，这些表位可被非自身反应性杀菌 mAb 识别。我们的假设是，非自身反应性抗荚膜单克隆抗体识别的 B 组荚膜表位与 N-Pr MBPS 化学合成过程中产生的 MBPS 衍生物相似或模仿，并且在宿主组织中很少存在（如果有的话）。 3) 基于MBPS衍生物和B组胶囊中鉴定的独特胶囊表位开发B组疫苗。我们的假设是，所鉴定的表位可用于设计引发杀菌、非自身反应性抗体的抗原。因此，该提案提供了一种开发基于 PS 的保护性疫苗的新方法，该疫苗可以避免引发自身抗体的安全问题，并有助于了解 B 组荚膜和宿主 PSA 抗原之间的结构差异。