Coronavirus neutralizing antibody epitopes and immunogens

项目2摘要 SARS-CoV-2大流行已经毫无疑问地确定了动物冠状病毒是对人类健康的主要潜在威胁。尽管预防和治疗SARS-CoV-2感染的疫苗和抗体以前所未有的速度发展，但蝙蝠和其他动物宿主中冠状病毒的反复出现突出了预防未来大流行的必要性。目前的疫苗是为了对抗SARS-CoV-2而设计的，但目前还不清楚它们在未来对传播的SARS-CoV-2人群中出现的变种以及重要的是对其他潜在的人畜共患冠状病毒的有效性。为了产生可以引发针对多种不同冠状病毒的广泛中和抗体的免疫原，我们首先需要了解冠状病毒包膜糖蛋白刺突上的哪些表位构成中和抗体的靶标。因此，本项目的第一个目标将是部署一系列基于VSV和HIV-1的假型病毒，以鉴定SARS-CoV-2恢复期或疫苗接种者血浆中发现的人中和抗体所靶向的SARS-CoV-2表位。此外，我们将确定这些表位在逐渐分化的冠状病毒中功能性保留的程度。在第二个目标中，我们将使用这些信息和其他信息来设计免疫原和免疫策略。我们将采用多种多价免疫原和递送方法，旨在延长抗原暴露并最大化抗体体细胞突变。这些实验的目标将是以最大可能的广度引发中和抗体的产生，并测试它们保护免受大流行威胁冠状病毒感染的能力。

ABSTRACT-PROJECT 2 The SARS-CoV-2 pandemic has established beyond doubt that animal coronaviruses are a major potential threat to human health. Although vaccines and antibodies to prevent and treat SARS-CoV-2 infection have been developed at unprecedented speed, the recurrent emergence of coronaviruses from bat and other animal reservoirs underlines the need for preparedness to prevent future pandemics. Current vaccines have been designed to combat SARS-CoV-2, but it is unclear how effective they will be in the future against emergent variants in circulating SARS-CoV-2 populations and, importantly, against other potentially zoonotic coronaviruses. To generate immunogens that can elicit broad neutralizing antibodies targeting multiple, distinct coronaviruses we need first to understand what epitopes on the coronavirus envelope glycoprotein spike constitute targets for neutralizing antibodies. Therefore, the first aim of this project will be to deploy an array of VSV-based and HIV-1 based pseudotyped and viruses to identify SARS-CoV-2 epitopes targeted by human neutralizing antibodies found in SARS-CoV-2 convalescent or vaccinee plasma. Additionally, we will determine to what extent these epitopes are functionally preserved in progressively more divergent coronaviruses. In the second aim, we will use this and other information to design immunogens and immunization strategies. We will employ a variety of multivalent immunogens and delivery methods aimed to prolong antigen exposure and maximize antibody somatic mutation. The goal of these experiments will be to elicit production of neutralizing antibodies with the maximum possible breadth, and test their ability to protect against infection by pandemic threat coronaviruses.