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.

摘要 新传播的A组链球菌（GAS）与其人类宿主之间的最初接触可以很容易地 被针对适当的GAS抗原（Ag）的抗体（Ab）阻碍。为了最好地模拟这个 微环境，生理的（即，低）GAS的接种剂量是必需的。本提案的目的是 鉴定最有效的单独的和代表多组分疫苗的组合的Ag 抗体介导的免疫靶点，并共同提供全球范围内的覆盖范围，对所有的GAS菌株。 所提出的方法的基本原理基于两个原则： 就在新GAS感染之前缺乏保护性Ab，且从大多数成人获得的血清至少具有 低水平的持续保护性抗体。后者是基于成人中GAS感染的发生率非常低， 这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 对从儿科血清分析中产生的保护性Ag特异性Ab（目的1）进行了实验测试， 小鼠（目的2）。分析感染前儿科血清是否缺乏针对主要候选疫苗的保护性Ab。 成人血清被用作纯化免疫球蛋白（IG）的来源，该免疫球蛋白特异于疫苗中缺失的靶抗原。 易感儿童免疫缺陷小鼠用纯化自成人的Ag特异性IG被动免疫 并用低感染剂量的GAS攻击。在小鼠中赋予保护作用的Ag特异性IG相当于 基于人血清保护相关物（CoP）。 在小鼠中对四种主要形式的GAS疾病进行建模并评估保护性免疫： 呼吸道感染、脓疱病、皮肤软组织感染和侵袭性疾病。三种气体 测试了菌株的主要亚群：咽喉专家、皮肤专家和通才。Ag目标 评估的是领先的候选疫苗，包括广泛和半保守的抗原以及表面和 分泌型Ags如果成功，这项工作将确定一系列Ag靶点，这些靶点可以作为 全球保护。它还将提供两个新的标准化平台-感染前人类血清筛查 Ab to GAS Ags和改进的小鼠模型-用于将来的鉴定和直接比较 其他GAS疫苗候选人。