Coronavirus neutralizing antibody epitopes and immunogens

摘要--项目2 SARS-CoV-2大流行毫无疑问地确立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反复出现冠状病毒，突显了为预防未来大流行做好准备的必要性。目前的疫苗是为对抗SARS-CoV-2而设计的，但目前尚不清楚它们在未来对传播中的SARS-CoV-2人群中的新变种以及重要的其他潜在人畜共患病冠状病毒的有效程度。为了产生能够诱导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尖峰上的哪些表位构成中和抗体的靶标。因此，该项目的第一个目标将是部署一系列基于VSV和基于HIV-1的假型和病毒，以识别在SARS-CoV-2恢复期或疫苗接种患者血浆中发现的人类中和抗体所针对的SARS-CoV-2表位。此外，我们将确定这些表位在多大程度上在逐渐分化的冠状病毒中得到功能保存。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。我们将使用多种多价免疫原和递送方法，旨在延长抗原暴露时间和最大限度地增加抗体体细胞突变。这些实验的目标将是以最大可能的广度诱导产生中和抗体，并测试它们抵御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.