Protective antibody in streptococcal infection models

摘要 新传播的A组链球菌(GAS)与其人类宿主之间的初始接触很容易 被针对适当GAS抗原的抗体(Ab)阻断。要最好地模拟这一点 微环境、生理(即低)接种量的气体是必不可少的。这项提议的目标是 单独和代表多组分疫苗的组合确定最有效的AGS 抗体介导的免疫靶点和集体可提供针对所有GAS菌株的全球覆盖范围。 提议的方法的基本原理基于两个原则：从儿童身上获得的血清 就在新的GAS感染之前，缺乏保护性抗体，从大多数成年人获得的血清至少有 低水平的持续性保护性抗体。后者是基于成人的气体感染发生率非常低， 可能是在生命早期反复感染后产生的保护性免疫的结果。假设 对儿童血清分析产生的保护性抗原特异性抗体(AIM 1)进行了实验测试 小鼠(目标2)。对感染前的儿科血清进行分析，以确定是否缺乏针对主要候选疫苗的保护性抗体。 成人血清用作针对疫苗目标AGS的纯化免疫球蛋白(Ig)的来源 易受影响的儿童。免疫缺陷小鼠用成人纯化的抗原特异性Ig被动免疫 并用低感染剂量的气体进行挑战。为小鼠提供保护的抗原特异性免疫球蛋白相当于 基于人血清的相关保护(COP)。 在小鼠身上建立了四种主要形式的气体疾病的模型，并对其进行了保护性免疫评估： 呼吸道感染、脓疱病、皮肤软组织感染和侵袭性疾病。来自这三家公司的天然气 主要的菌株亚群进行了测试：咽喉专家、皮肤专家和多面手。银靶 被评估的是领先的候选疫苗，包括广泛和半保守的AGS以及表面和 秘密的AGS。如果成功，这项工作将确定一组可以作为基础的银靶 全球保护。它还将提供两个新的标准化平台-感染前人血清的筛选 AB到GAS AGS和改进的小鼠模型-用于将来的识别和直接比较 额外的天然气疫苗候选者。

ABSTRACT The initial contact between newly transmitted group A streptococci (GAS) and its human host can be readily thwarted by antibody (Ab) directed to the appropriate GAS antigens (Ags). To best simulate this microenvironment, physiological (i.e., low) inoculum doses of GAS are essential. The goal of this proposal is to identify Ags, alone and in combinations representing multicomponent vaccines, that are the most effective targets of Ab-mediated immunity and collectively can provide worldwide coverage against all GAS strains. The underlying rationale for the proposed approach rests on two principles: That serum obtained from children just prior to a new GAS infection lacks protective Ab, and that serum obtained from most adults has at least low levels of persisting protective Ab. The latter is based on the very low incidence of GAS infection in adults, likely the result of protective immunity that developed following repeated infections earlier in life. Hypotheses on protective Ag-specific Ab generated from analysis of pediatric serum (aim 1) are experimentally tested in mice (aim 2). Pre-infection pediatric serum is analyzed for lack of protective Ab to leading vaccine candidates. Adult serum is used as a source for purified immunoglobulin (Ig) specific to the vaccine target Ags missing in susceptible children. Immunodeficient mice are passively immunized with the Ag-specific Ig purified from adults and challenged with low infective doses of GAS. The Ag-specific Ig that confers protection in mice equates to a human serum-based correlate of protection (CoP). Four major forms of GAS disease are modeled in mice and evaluated for protective immunity: upper respiratory tract infection, impetigo, skin and soft tissue infection and invasive disease. GAS from all three major subpopulations of strains are tested: throat specialists, skin specialists and generalists. The Ag targets evaluated are leading vaccine candidates and include broadly and semi-conserved Ags as well as surface and secreted Ags. If successful, this work will identify a collection of Ag targets that can serve as the basis for global protection. It will also deliver two new standardized platforms – screening of pre-infection human serum Ab to GAS Ags and improved mouse models - for future identification and straightforward comparison of additional GAS vaccine candidates.