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