Cross-Protective Humoral Immunity to Coronavirus

对冠状病毒的交叉保护性体液免疫

• 批准号: 10842888
• 负责人: Duane R. Wesemann
• 金额: $ 317.59万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-16 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10842888
• 关键词: 2019-nCoV; Address; Animals; Antibodies; Antibody Response; Antigens; B-Lymphocytes; COVID-19; COVID-19 patient; COVID-19 vaccination; COVID-19 vaccine; Cells; Clinical; Containment; Coronavirus; Data; Dose; Effectiveness; Escape Mutant; Exhibits; Family; Future; Genetic Drift; Goals; Hand; Heterogeneity; Human; Humoral Immunities; Immune; Immune response; Immunity; Immunologic Memory; Immunologics; Infection; Knowledge; Learning; Light; Literature; Maps; Mediating; Memory B-Lymphocyte; Modeling; Outcome; Population; Preclinical Testing; Preparation; Process; Property; Proteins; Research; Research Personnel; Role; SARS-CoV-2 infection; SARS-CoV-2 variant; Serology; Somatic Mutation; Source; Testing; Training; Translating; Vaccination; Vaccinee; Vaccines; Virus; Work; cohort; coronavirus vaccine; cross reactivity; design; efficacy evaluation; in vivo; next generation; novel coronavirus; novel vaccines; pathogen; pre-clinical; prevent; programs; protective efficacy; response; severe COVID-19; synergism; tool; universal coronavirus vaccine; vaccine delivery; vaccine development; vaccine evaluation; vaccine strategy; zoonotic coronavirus

PROJECT 1 SUMMARY Global establishment of Severe Acute Respiratory Syndrome (SARS) Coronavirus (CoV)-2 is a continued human threat. While successful vaccine programs are well underway, genetic drift and immune escape have already begun to subvert immunity. In addition, related zoonotic coronaviruses threaten transition into the human population. CoVs can be highly transmissible and highly lethal, posing a grave threat to human lives and world economies. In this light, developing pan-CoV vaccine options in preparation for the expected broad range of SARS-CoV-2 variants and future emergent coronaviruses could save millions of lives and prevent future global catastrophes. While current SARS-CoV-2 vaccines targeting the virus spike (S) protein hold great promise in providing protection against current circulating strains, research is urgently needed to understand breadth and durability of immunity across the CoV family and to translate this information into next generation vaccines with increased breadth to cover SARS-CoV-2 escape mutants as well as to address emergent CoVs. The overall goal of this program is to produce critical information necessary for the design and testing of next generation CoV vaccine strategies with the greatest possible breadth across the CoV family. The Program team will identify humoral, cellular, and structural immunologic features influencing clinical outcomes and immune recognition breadth in human SARS-CoV-2 infection and human vaccination cohorts to fuel design and pre-clinical testing of protective coronavirus vaccine strategies to identify those with the greatest possible breadth. Project 1’s goal in this process is to define B cell/serologic properties of broad CoV immunity and identify vaccine delivery conditions that can best support them. Preliminary discoveries from Project 1 together with recent literature support the working hypothesis that aspects of vaccine strategy such as antigen choice, delivery timing, dose, and valency will influence CoV recognition breadth and effectiveness. Knowledge gained from strategic analysis of the heterogeneity of active human SARS-CoV-2 convalescent and vaccine cohorts will generate new hypotheses to integrate into pre-clinical vaccine testing approach. In particular, recent work from Project 1 investigators has identified the conserved S2 domain as promising target for broad CoV immunity in humans. Program 1’s roles in evaluating these hypotheses are to: 1) identify immune correlates of convalescent COVID-19 patients and vaccinees that exhibit superior durability and cross-reactivity; 2) define the mechanisms of cross-reactive monoclonal mediated protection against CoVs in vivo; and 3) evaluate the efficacy of novel vaccine immunogens to induce protective B cell/functional serological responses in animals. Supported by Core B, results from Project 1 will provide strategic antibody, serological and memory B cell analysis in the context of an integrative programmatic approach in synergy with Projects 2 and 3 approach to generate vaccine strategies with maximal breadth and effectiveness.

项目1摘要 全球建立严重的急性呼吸综合征（SARS）冠状病毒（COV）-2是一个续 人类威胁。尽管成功的疫苗计划正在进行中，但遗传漂移和免疫逃生已有 已经开始颠覆免疫力。此外，相关的人畜共努性冠状病毒威胁到过渡到 人口。 COV可以高度传播和高度致命，对人类的生命构成严重威胁 和世界经济。从这个角度来看，开发Pan-COV疫苗的选择以准备预期的广阔 SARS-COV-2变体和未来新兴冠状病毒的范围可以挽救数百万的生命并防止 未来的全球灾难。而靶向病毒尖峰（S）蛋白的当前SARS-COV-2疫苗可得到 迫切需要进行研究，以防止当前循环菌株提供保护 整个COV家族的免疫力的广度和耐用性，并将这些信息转化为下一代 宽度增加以覆盖SARS-COV-2逃生突变体以及解决新兴COV的疫苗。 该计划的总体目标是生成针对下一个设计和测试所必需的关键信息 COV家族中最广度的COV疫苗策略发电。该程序 团队将确定影响临床结果和的体液，细胞和结构免疫学特征 人类SARS-COV-2感染和人类疫苗队列中的免疫识别宽度与燃料设计 以及受保护冠状病毒疫苗策略的临床前测试，以确定最大可能的人 宽度。项目1在此过程中的目标是定义B细胞/血清学特性广泛的COV免疫和 确定最能支持它们的疫苗输送条件。项目1的初步发现 最近的文献支持了以下假设，即疫苗策略的各个方面（例如抗原选择）， 交付时机，剂量和价值将影响COV的识别范围和有效性。知识获得了 从活跃的人类SARS-COV-2康复和疫苗队列的异质性的战略分析中 将产生新的假设，以整合到临床前疫苗测试方法中。特别是最近的工作 从项目1中，调查人员将配置的S2域确定为宽COV的承诺目标 人类的免疫力。程序1在评估这些假设中的作用是：1）确定免疫相关性 康复性共同19岁的患者和疫苗暴露了较高的耐用性和交叉反应性； 2）定义 交叉反应单克隆介导的对COV在体内的保护的机制； 3）评估 新型疫苗免疫原的功效可诱导动物的受保护的B细胞/功能血清学反应。 在核心B的支持下，项目1的结果将提供战略性抗体，血清学和记忆B细胞 在项目2和3 生成具有最大宽度和有效性的疫苗策略。