Chemistry and Immunology of Streptococcal M Proteins

描述(由申请人提供)：本项目的总体目标是 开发一种安全且广泛有效的疫苗，以预防A群 链球菌感染。此前的研究表明，表面M 蛋白质是主要的保护性抗原，含有组织交叉反应。 表位和保护性表位。血清型特异性保护性 表位可以从潜在有害的自身免疫表位分离出来 M蛋白N端肽的限制性。保护性M蛋白片段 代表A组链球菌的多种血清型的链球菌然后可以组合成 形成多价疫苗。这项建议的具体目的是：1) 确定M蛋白或其他表面蛋白的一级结构 含有A组链球菌血清型的调理(保护性)表位 在流行病学上很重要，因此有必要接种疫苗 成分，2)构建重组多价疫苗，唤起 26种不同抗体在实验动物中的最佳反应 A群链球菌的血清型，3)免疫兔血清的检测 抗临床特异性抗体和杀菌抗体的多价疫苗 10例儿童咽炎患者分离的A群链球菌 美国的地理位置，4)开发鼻腔给药策略 基于多价M蛋白的疫苗导致分泌性和系统性 免疫反应，和5)直接比较保护性免疫原性 基于多价M蛋白的疫苗通过以下两种途径之一接种给小鼠 肌肉内或鼻腔途径。在我们的初步研究中，我们有 确定A组链球菌的6个流行病学重要血清型 其不被针对N-末端M蛋白多肽的抗血清调理。 我们提出了一系列实验来确定该分子的共价结构 M蛋白、类M蛋白或其他含有调理物质的表面蛋白 表位，以便这些M血清型可以包括在多价疫苗中。我们 将构建一种26价疫苗，由4种不同的重组、杂交 蛋白质。将对单个杂交蛋白进行保护性和 兔肌肉注射后的组织交叉反应免疫原性。 因为粘膜递送的链球菌疫苗可能既有免疫学上的 和非肠道分娩的实际优势，我们将评估不同的 鼻腔给药的策略，然后直接比较保护性 I.N.的功效。VS I.M.在老鼠身上接种疫苗。这些研究应该提供 开发安全有效的多价疫苗所需的详细信息 这可以预防北美的大多数链球菌感染 和西欧。

DESCRIPTION (provided by the applicant): The overall goal of this project is to develop a safe and broadly effective vaccine that will prevent group A streptococcal infections. Previous studies have shown that the surface M proteins, which are the major protective antigens, contain tissue-crossreactive epitopes as well as protective epitopes. The serotype-specific protective epitopes may be separated from potentially harmful autoimmune epitopes by using limited N-terminal peptides of M proteins. The protective M protein fragments representing multiple serotypes of group A streptococci may then be combined to form a multivalent vaccine. The specific aims of this proposal are: 1) To identify the primary structures of M proteins or other surface proteins that contain opsonic (protective) epitopes from serotypes of group A streptococci that are epidemiologically important and, therefore, necessary vaccine components, 2) To construct recombinant, multivalent vaccines that evoke optimal opsonic antibody responses in laboratory animals against 26 different serotypes of group A streptococci, 3) To test immune rabbit sera evoked by multivalent vaccines for opsonic and bactericidal antibodies against clinical isolates of group A streptococci collected from children with pharyngitis in 10 geographic sites in the U.S., 4) To develop strategies of intranasal delivery of multivalent M protein-based vaccines that result in secretory and systemic immune responses, and 5) To directly compare the protective immunogenicity of multivalent M protein-based vaccines delivered to mice via either the intramuscular or intranasal routes. In our preliminary studies, we have identified six epidemiologically important serotypes of group A streptococci that are not opsonized by antisera against the N-terminal M protein peptides. We propose a series of experiments to determine the covalent structures of the M proteins, M-like proteins, or other surface proteins that contain opsonic epitopes so that these M serotypes may be included in multivalent vaccines. We will construct a 26-valent vaccine composed of 4 different recombinant, hybrid proteins. The individual hybrid proteins will be tested for protective and tissue-crossreactive immunogenicity after intramuscular injection of rabbits. Because mucosal delivery of streptococcal vaccines may have both immunological and practical advantages over parenteral delivery, we will assess different strategies of intranasal delivery and then directly compare the protective efficacy of i.n. vs i.m. vaccines in mice. The studies should provide the detailed information needed to develop a safe and effective multivalent vaccine that could prevent the majority of streptococcal infections in North America and Western Europe.