Understanding antibody responses and defining correlates of protection for endemic and pandemic coronavirus strains

SARS-CoV-2大流行是一场特殊的公共卫生危机，突显了需要更好地 对控制广泛的保护性免疫反应和产生的机制的理解 能够引起这种反应的候选疫苗。题为《编程持久》的方案项目 对冠状病毒的免疫(冥王星)“提出了一个全面的研究计划，以设计泛 深度B细胞广泛保护的肉瘤病毒和泛-贝塔冠状病毒疫苗 在连续接种疫苗的冠状病毒免疫史背景下的特征 和/或感染。两个互补的研究项目将建立健壮、持久的 和保护性冠状病毒体液免疫(项目1)以及病毒的设计和测试效果 防变异的泛肉瘤病毒和泛贝塔冠状病毒疫苗(项目2)。这些核心将与 这两个研究项目支持了研究目标的圆满完成。行政部门 CORE将管理财团，协调跨项目活动，并创建结构和 实现冥王星目标所需要的环境。抗体核心公司将开发大量的 抗冠状病毒刺突蛋白重组单抗(MAbs)的特异性和特异性 冠状病毒感染和/或接种在人和动物中引起的免疫反应的呼吸 模特们。动物模型核心将提供一个中央资源，包括批准、设施和专业知识 评估广谱交叉反应冠状病毒抗体和疫苗在强健的临床前的有效性 针对一系列冠状病毒的模型，包括选择代理。研究项目将 相互协作，并与抗体和动物模型核心合作，由 管理核心。项目1将侧重于确定B细胞对冠状病毒感染的反应和 接种疫苗。在项目1中，我们将把异常独特的临床标本与我们深入的 B细胞在单细胞水平上的反应动力学和原子分辨率下的特异性 为确定保护性免疫的相关因素提供一个可靠的平台。由此产生的结构数据将 为开发“通用”冠状病毒疫苗提供关键信息(与 项目2)。一个由来自五个机构的多学科科学家组成的团队，他们有突出的成就 合作记录将进行拟议的研究。一体化与协同化 跨项目和核心的活动将推动计划项目的成功完成 雄心勃勃的研究议程，使冥王星能够实现开发防变异的长期目标 泛肉瘤病毒和泛贝塔冠状病毒疫苗。这些发现将有助于遏制当前的 SARS-CoV-2大流行，减少未来冠状病毒大流行的风险。

The SARS-CoV-2 pandemic represents an exceptional public health crisis highlighting the need for better understanding of the mechanisms controlling broadly protective immune responses and generating vaccine candidates able to elicit such responses. The program project entitled “Programming Long-lasting Immunity to Coronaviruses (PLUTO)” proposes a comprehensive research plan towards designing pan- sarbecovirus and pan-betacoronavirus vaccines with broad protection by applying in-depth B cell characterization in the context of coronavirus immune histories imprinted by successive vaccinations and/or infections. Two complementary research projects will establish correlates of robust, durable and protective coronavirus humoral immunity (Project 1) as well as design and test efficacy of viral variant-proof pan-sarbecovirus and pan-betacoronavirus vaccines (Project 2). The Cores will synergize with the two research projects to support the successful completion of the research aims. The Administrative Core will manage the consortium, coordinate cross-project activities, and create the structure and environment needed to accomplish PLUTO's goals. The Antibody Core will develop large panels of recombinant monoclonal antibodies (mAbs) against coronavirus spike proteins to define specificity and breath of immune responses elicited by coronavirus infections and/or vaccinations in humans and animal models. The Animal Model Core will provide a central resource with approvals, facilities, and expertise to assess efficacy of broadly cross-reactive coronavirus antibodies and vaccines in robust pre-clinical models against a spectrum of coronaviruses, including Select Agents. The Research Projects will collaborate with each other and with the Antibody and Animal Model Cores, coordinated by the Administrative Core. Project 1 will focus on defining B cell responses to coronavirus infection and vaccination. In Project 1, we will pair exceptionally unique clinical specimens with our in-depth interrogation of B cell response dynamics at the single cell level and specificity at atomic resolution to provide a robust platform for identifying correlates of protective immunity. The resulting structural data will provide key information towards the development of a “universal” coronavirus vaccine (in collaboration with Project 2). A multidisciplinary team of scientists from five institutions who have an outstanding track record of working collaboratively will conduct the proposed studies. The integrated and synergistic activities across Projects and Cores will drive the successful completion of the program project's ambitious research agenda, enabling achievement of the long-term PLUTO goal of developing variant-proof pan-sarbecovirus and pan-betacoronavirus vaccines. These findings will contribute to curbing the current SARS-CoV-2 pandemic and mitigate the risk of future pandemics with coronaviruses.