Cross-Protective Humoral Immunity to Coronavirus

项目1概要 严重急性呼吸系统综合症（SARS）冠状病毒（CoV）-2的全球建立仍在继续 人类威胁。虽然成功的疫苗计划正在顺利进行，但遗传漂变和免疫逃逸已经成为一种新的挑战。 已经开始破坏豁免权了。此外，相关的人畜共患冠状病毒威胁着向 人口。冠状病毒可高度传播和高度致命，对人类生命构成严重威胁 和世界经济。有鉴于此，开发泛冠状病毒疫苗选择，为预期的广泛流行做准备， 一系列SARS-CoV-2变异体和未来出现的冠状病毒可以挽救数百万人的生命， 未来的全球性灾难。虽然目前针对病毒刺突蛋白（S）的SARS-CoV-2疫苗具有很大的优势， 在提供针对当前流行菌株的保护方面，迫切需要研究来了解 整个CoV家族免疫力的广度和持久性，并将这些信息转化为下一代 扩大疫苗的覆盖范围，以涵盖SARS-CoV-2逃逸突变体以及应对新出现的CoV。 该计划的总体目标是为下一步的设计和测试提供关键信息 新一代CoV疫苗策略在CoV家族中具有最大可能的广度。程序 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感染和人类疫苗接种队列中免疫识别宽度 和保护性冠状病毒疫苗策略的临床前测试，以确定那些最大可能的 宽度项目1在该过程中的目标是确定广泛CoV免疫的B细胞/血清学特性， 确定能够最好地支持他们的疫苗提供条件。项目1的初步发现 最近的文献支持了疫苗策略的各个方面如抗原选择， 递送时间、剂量和效价将影响CoV识别广度和有效性。获得的知识 根据对活动性人SARS-CoV-2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 来自项目1的研究人员已经将保守的S2结构域确定为广泛CoV的有希望的靶点 人类的免疫力。程序1在评估这些假设中的作用是：1）识别免疫相关性， 恢复期COVID-19患者和疫苗接种者表现出优异的上级耐久性和交叉反应性; 2）定义 交叉反应性单克隆介导的体内抗CoV保护机制;以及3）评估 新疫苗免疫原在动物中诱导保护性B细胞/功能性血清学应答的效力。 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方法协同作用的综合方案方法背景下进行的分析， 制定最广泛和最有效的疫苗战略。

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.