Epitope and mechanistic correlates of broadly protective human antibodies for pneumococcal infection

肺炎球菌感染的广泛保护性人类抗体的表位和机制相关性

• 批准号: 10566691
• 负责人: Jarrod Mousa
• 金额: $ 75.59万
• 依托单位: UNIVERSITY OF GEORGIA
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-11-01 至 2027-10-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10566691
• 关键词: Acute; Address; Adhesions; Agglutination; Antibiotic Resistance; Antibodies; Antigen Targeting; Antigens; Asthma; B-Lymphocytes; Bacteremia; Bacteria; Bacterial Pneumonia; Binding; Cardiovascular Diseases; Cells; Cessation of life; Chronic Obstructive Pulmonary Disease; Clinical Trials; Communicable Diseases; Complement; Coupled; Cryoelectron Microscopy; Data; Death Rate; Deposition; Development; Diabetes Mellitus; Disease Management; Elderly; Encapsulated; Epitopes; Exhibits; Failure; Frequencies; Growth; HIV; Human; Immunologics; In Vitro; Incidence; Individual; Infection; Interferometry; Invaded; Lung; Macrophage; Mediating; Membrane Proteins; Meningitis; Microbial Biofilms; Modeling; Monoclonal Antibodies; Mus; Mutation; Nasopharynx; National Institute of Allergy and Infectious Disease; Otitis Media; Pathway interactions; Pharmaceutical Preparations; Pneumococcal Colonization; Pneumococcal Infections; Pneumococcal Pneumonia; Pneumococcal vaccine; Pneumonia; Polysaccharides; Prevention; Proteins; Protocols documentation; Readiness; Research; Role; Serotyping; Specificity; Streptococcus pneumoniae; Techniques; Therapeutic; United States National Institutes of Health; Vaccines; Work; X-Ray Crystallography; high risk population; human monoclonal antibodies; improved; in vivo; infection rate; infectious disease treatment; influenza infection; innovation; mouse model; neutrophil; novel therapeutics; pandemic influenza; pathogen; pathogenic bacteria; prevent; prophylactic; protective efficacy; structural determinants; synergism; vaccine efficacy

Streptococcus pneumoniae is a leading infectious pathogen, causing pneumonia, bacteremia, meningitis, acute otitis media, and nearly one million deaths worldwide each year. S. pneumoniae can be carried in the nasopharynx asymptomatically, which contributes to pathogen spread, as pneumococcal carriage often precedes active infection. Infections occur with increased frequency in high-risk populations, such as individuals with diabetes, asthma, chronic obstructive pulmonary disease, cardiovascular disease, and HIV. Several vaccines are currently in use to prevent pneumococcal infection; however, several factors warrant further research, including limited serotype coverage of current vaccines, limited vaccine efficacy against some vaccine- included serotypes, increased incidence of colonization and infection with non-vaccine serotypes, and widespread drug and multidrug antibiotic resistance among non-vaccine serotypes. This R01 proposal will address these limitations by defining the structural determinants mediating the serotype breadth and protective efficacy of broadly-reactive human mAbs that prevent and treat pneumococcal infection. The scientific premise of this proposal is that mAbs to conserved pneumococcal antigens that are broadly reactive could serve as priority or adjunctive therapies for pneumococcal disease management. This proposal will focus on mAbs to pneumococcal antigens that are highly conserved and are targets of B cells during pneumococcal colonization and infection. Our work will advance the field by generating new therapeutic options for the prevention and treatment of pneumococcal infection for diverse serotypes, including encapsulated and nonencapsulated serotypes, and by identifying protective epitopes on pneumococcal surface proteins. Our innovative hypothesis is that human mAbs targeting conserved pneumococcal surface proteins will exhibit substantial serotype breadth, can treat pneumococcal infection, and that mAb protective efficacy and serotype breadth is correlated to epitope specificity. Our data will provide new findings for the pneumococcal protein vaccine field. In Aim 1, the serotype breadth and protective efficacy of human mAbs targeting conserved protein antigens will be determined in models of both primary and secondary (following influenza virus infection) pneumococcal infection. In Aim 2, we will define the epitopes mediating the protective efficacy of the human mAbs using X-ray crystallography and cryo-EM, which will be critical to the field by informing the development of protein-based pneumococcal vaccines, as we have shown in our preliminary data that the epitope on pneumococcal proteins impacts mAb breadth and protective efficacy. In Aim 3, we will conduct in depth in vitro and in vivo mechanistic studies to assess mAb functions, including opsonophagocytic and agglutination activity, and inhibition of bacterial growth, adhesion, invasion, and biofilm formation. We will also assess the specific immunological pathways important for mAb-mediated bacterial clearance. Overall, our work is both practically and conceptually innovative, and will challenge current treatment paradigms for pneumococcal infection.

肺炎链球菌是一种主要的传染性病原体，可引起肺炎、菌血症、脑膜炎、急性 中耳炎，全世界每年有近百万人死亡。肺炎链球菌可携带于 鼻咽部无症状，这有助于病原体传播，因为肺炎球菌经常携带 先于活动性感染。在高危人群（例如个人）中，感染发生的频率增加 患有糖尿病、哮喘、慢性阻塞性肺病、心血管疾病和艾滋病毒。一些 目前正在使用疫苗来预防肺炎球菌感染；然而，有几个因素需要进一步 研究，包括现有疫苗的血清型覆盖范围有限，针对某些疫苗的疫苗功效有限 包括血清型、非疫苗血清型定植和感染发生率增加，以及 非疫苗血清型中普遍存在药物和多药抗生素耐药性。该 R01 提案将 通过定义介导血清型广度的结构决定因素来解决这些限制 具有广泛反应性的人单克隆抗体预防和治疗肺炎球菌感染的保护功效。这 该提案的科学前提是针对具有广泛反应性的保守肺炎球菌抗原的单克隆抗体 可作为肺炎球菌疾病管理的优先或辅助疗法。该提案将重点 针对肺炎球菌抗原的单克隆抗体高度保守，是肺炎球菌期间 B 细胞的靶标 定植和感染。我们的工作将通过为该领域提供新的治疗选择来推动该领域的发展 预防和治疗不同血清型的肺炎球菌感染，包括荚膜和肺炎球菌 非封装血清型，并通过识别肺炎球菌表面蛋白上的保护性表位。我们的 创新的假设是，针对保守的肺炎球菌表面蛋白的人类单克隆抗体将表现出 血清型广泛，可治疗肺炎球菌感染，且单克隆抗体的保护功效与血清型有关 宽度与表位特异性相关。我们的数据将为肺炎球菌蛋白提供新的发现 疫苗领域。在目标 1 中，针对保守蛋白的人单克隆抗体的血清型广度和保护功效 将在原发性和继发性模型（流感病毒感染后）中测定抗原 肺炎球菌感染。在目标 2 中，我们将定义介导人类保护功效的表位 使用 X 射线晶体学和冷冻电镜的单克隆抗体，这对于该领域的开发至关重要 基于蛋白质的肺炎球菌疫苗，正如我们在初步数据中所示，表位 肺炎球菌蛋白影响单克隆抗体的广度和保护功效。目标3，我们将在体外深入进行 以及评估单克隆抗体功能的体内机制研究，包​​括调理吞噬和凝集活性， 抑制细菌生长、粘附、侵袭和生物膜形成。我们还将评估具体情况 免疫学途径对于单克隆抗体介导的细菌清除很重要。总的来说，我们的工作既实用又实用 概念上具有创新性，并将挑战当前肺炎球菌感染的治疗模式。