Cross-Protective Humoral Immunity to Coronavirus

项目1总结 严重急性呼吸系统综合症(SARS)冠状病毒(CoV)-2在全球范围内的建立仍在继续 人类的威胁。虽然成功的疫苗计划正在顺利进行，但基因漂移和免疫逃逸 已经开始颠覆豁免权。此外，相关的人畜共患冠状病毒有可能过渡到 人类人口。冠状病毒具有高度传染性和高度致命性，对人类生命构成严重威胁。 和世界经济。鉴于此，开发泛冠状病毒疫苗选择为预期的广泛 一系列SARS-CoV-2变种和未来出现的冠状病毒可以拯救数百万人的生命，防止 未来的全球灾难。而目前针对病毒尖峰(S)蛋白的SARS-CoV-2疫苗效果很好 承诺提供对当前流行毒株的保护，迫切需要研究来了解 整个冠状病毒家族免疫的广度和持久性，并将这一信息转化为下一代 疫苗的广度增加，以涵盖SARS-CoV-2逃逸突变以及应对紧急CoV。 该计划的总体目标是为Next的设计和测试提供必要的关键信息 新一代冠状病毒疫苗战略在整个冠状病毒家族中具有最大可能的广度。该计划 研究小组将确定影响临床结果的体液、细胞和结构免疫学特征 人类SARS-CoV-2感染的免疫识别广度和人类疫苗队列燃料设计 以及临床前对保护性冠状病毒疫苗策略的测试，以确定哪些人具有最大可能的 广度。S在这个过程中的目标是确定广泛冠状病毒免疫的B细胞/血清学特性和 确定最能支持他们的疫苗投放条件。来自项目1的初步发现 根据最近的文献支持的工作假说，疫苗策略的各个方面，如抗原选择， 给药时机、剂量和效价将影响冠状病毒识别的广度和有效性。获得的知识 来自SARS-CoV-2活动性恢复期和疫苗队列异质性的战略分析 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，研究人员已经确定保守的S2结构域是广泛覆盖的有希望的靶点 人类的免疫力。S在评估这些假说中的作用是：1)确定免疫相关性 新冠肺炎恢复期患者和表现出卓越耐久性和交叉反应性的疫苗接种者；2)定义 交叉反应单抗介导的体内抗冠状病毒保护机制；3)评价 新型疫苗免疫原在动物体内诱导保护性B细胞/功能性血清学反应的有效性。 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 在与项目2和3协同的综合方案办法的背景下进行分析 制定具有最大广度和有效性的疫苗策略。

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.