Human antibody-based countermeasures against the Wuhan Coronavirus SARS-CoV-2

项目摘要 严重急性呼吸综合征冠状病毒2（SARS-CoV-2）是一种正链RNA病毒 它于2019年12月在中国武汉首次被隔离。SARS-CoV-2是冠状病毒疾病的病因 2019年（COVID-19），现在是一场大流行病，已造成130多万确诊病例和72，000 死亡，估计病死率为4%，老年人的死亡率高得多（约15%）， 免疫力低下几乎所有国家和地区都报告了病例，主要流行在中国， 意大利、西班牙、法国、德国、伊朗和美国。SARS-CoV-2被认为是人畜共患病的起源，大多数 很可能是蝙蝠，与最初的SARS冠状病毒有75%的相同性。大多数病例是通过人与人之间的直接传播 人类传播，并描述了在无症状个体中的社区传播。当前没有任何 反制措施是许可给人类使用的。的开发、表征和最终部署 基于抗体的SARS-CoV-2治疗可以预防大量的发病率和死亡率， 可能会减缓疫情的蔓延这一交互式多PI提案利用了以下方面的互补专业知识 Diamond、Crowe和Baric实验室迅速开发出高度中和和治疗性的人类 针对SARS-CoV-2的单克隆抗体（mAb），可立即用于人类。为了实现这一目标，我们将 产生并询问抗SARS-CoV-2的人mAb，所述人mAb从多个恢复期的 科目我们将通过选择天然存在的， 通过库测序和同胞分析鉴定的体细胞变体和Fc效应子功能。保护 顶级候选冠状病毒mAb的活性将在新生成和优化的小鼠模型中进行测试， SARS-CoV-2感染，包括表达人ACE 2受体（hACE 2）的感染。定义的相关性 保护，我们将使用嵌合病毒，鸟枪诱变，中和逃逸，以确定表位 最具保护性的单克隆抗体我们的团队在生成、表征和 优化抗体、CoV生物学以及疾病和保护的动物模型。一种治疗方法， 一至三种高度中和的单克隆抗体可提供立即对抗大流行传播的对策 并帮助建立结构和功能性体液保护的相关性， 为疫苗接种工作提供信息。

Project Summary Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a positive-sense single-stranded RNA virus that was first isolated in Wuhan China in December, 2019. SARS-CoV-2 is the cause of coronavirus disease 2019 (COVID-19), which is now a pandemic and has caused more than 1.3 million confirmed cases and 72,000 deaths, with an estimated case fatality rate of 4%, with substantially higher death rates (~15%) in the elderly or immunocompromised. Virtually all countries and territories have reported cases, with major epidemics in China, Italy, Spain, France, Germany, Iran, and the United States. SARS-CoV-2 is thought to be of zoonotic origin, most likely bats, and is about 75% identical to the original SARS-CoV. Most cases are spread by direct human-to- human transmission, with community transmission in asymptomatic individuals described. Currently, no countermeasures are licensed for human use. The development, characterization, and ultimately deployment of an antibody-based treatment against SARS-CoV-2 could prevent substantial morbidity and mortality, and possibly mitigate its epidemic spread. This interactive multi-PI proposal leverages complementary expertise in the Diamond, Crowe, and Baric laboratories to rapidly develop highly neutralizing and therapeutic human monoclonal antibodies (mAbs) against SARS-CoV-2 for immediate use in humans. To achieve this goal, we will generate and interrogate human mAbs against SARS-CoV-2 that are obtained from multiple convalescent subjects. We will identify potently neutralizing mAbs and optimize them for affinity by selecting naturally occurring somatic variants identified by repertoire sequencing and sibling analysis and Fc effector functions. Protective activity of top candidate coronavirus mAbs will be tested in newly-generated and optimized mouse models of SARS-CoV-2 infection, including those expressing human ACE2 receptors (hACE2). To define correlates of protection, we will use chimeric viruses, shotgun mutagenesis, and neutralization escape to identify the epitopes of our most protective mAbs. Our team has extensive experience in the generation, characterization and optimization of antibodies, CoV biology, and animal models of disease and protection. A therapy composed of one to three highly neutralizing mAbs may provide an immediate countermeasure against the pandemic spread of SARS-CoV-2 and help establish correlates of structural and functional humoral protection that ultimately inform vaccine efforts.