Protective antibody in streptococcal infection models

链球菌感染模型中的保护性抗体

• 批准号: 10576491
• 负责人: Debra E BESSEN
• 金额: $ 59.39万
• 依托单位: NEW YORK MEDICAL COLLEGE
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-12-02 至 2027-11-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10576491
• 关键词: Abbreviations; Accounting; Active immunity; Adult; Age; Animal Model; Animals; Antibodies; Antibody-mediated protection; Antigen Targeting; Antigens; Autoimmune Diseases; Bacteria; Binding; Biological; Carbohydrates; Cessation of life; Child; Childhood; Clinical Trials; Collection; Colony-forming units; Complex; Data; Development; Disease; Disease model; Dose; Elements; Epidemiological trend; Epithelium; Equation; Exhibits; Failure; Fibronectins; Future; General Practitioners; Goals; Habitats; Human; Immune response; Immunity; Immunize; Immunodeficient Mouse; Immunoglobulins; Immunologic Deficiency Syndromes; Impetigo; Incidence; Infection; Lead; Life; Lymphoid Tissue; Measures; Modeling; Morbidity - disease rate; Mus; Nose; Organ; Passive Immunity; Passive Immunization; Pharyngeal structure; Physiological; Plasminogen; Predisposition; Resources; Rest; Route; Secretory Immunoglobulin A; Serology; Serum; Severe Combined Immunodeficiency; Skin; Skin Tissue; Soft Tissue Infections; Source; Specialist; Specificity; Specimen; Standardization; Streptococcal Infections; Streptococcal Vaccines; Streptococcus; Streptococcus pyogenes; Streptolysins; Surface; Swab; Testing; Upper Respiratory Infections; Upper respiratory tract; Vaccines; Virulence; Virulence Factors; Work; comparison group; flexibility; human disease; human subject; human tissue; humanized mouse; immunodeficient mouse model; immunoreactivity; improved; longitudinal, prospective study; mortality; mouse model; multiple myeloma M Protein; novel; pathogen; preclinical development; protective efficacy; relative effectiveness; screening; transmission process; vaccine candidate; vaccine development; wound

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.

抽象的 新传输组A链球菌（GAS）及其人类宿主之间的初步接触很容易 由针对适当气体抗原（AGS）的抗体（AB）挫败。最好模拟这个 微环境，生理（即低）水剂量的气体至关重要。该提议的目的是 识别最有效的AG，单独和代表多组分疫苗的组合 AB介导的免疫和统称的目标可以为所有气体菌株提供全球覆盖率。 拟议方法的基本原理取决于两个原则：从儿童那里获得的血清 就在新的气体感染之前，缺乏受保护的AB，而从大多数成年人获得的血清至少具有 持续保护的AB的较低水平。后者基于成人气体感染的非常低的事件， 保护性免疫的结果可能是在生命早期反复感染后产生的。假设 在小儿血清分析中产生的受保护的Ag特异性AB（AIM 1）在实验中测试 小鼠（目标2）。分析了感染前的小儿血清，因为缺乏候选疫苗的AB缺乏受保护的AB。 成年血清被用作特定于疫苗目标AG缺失的纯化免疫球蛋白（IG）的来源 易感儿童。免疫缺陷小鼠用成人纯化的Ag特异性Ig被动免疫 并以低感染剂量的气体挑战。承认小鼠保护的Ag特异性IG等于A 基于人血清保护的相关性（COP）。 在小鼠中建模了四种主要形式的气体疾病，并评估了受保护的免疫力：上部 呼吸道感染，推，皮肤和软组织感染和侵入性疾病。这三个的气体 测试了菌株的主要亚群：喉咙专家，皮肤专家和通才。 AG目标 评估的是候选疫苗的领先疫苗，包括广泛和半保守的AG以及表面以及 分泌的AGS。如果成功，这项工作将确定可以作为可以作为基础的AG目标的集合 全球保护。它还将提供两个新的标准化平台 - 筛选感染前的人类串行 AB到气体AGS和改进的小鼠模型 - 用于将来的识别和直接比较 额外的气体疫苗候选物。