Human antibody-based countermeasures against the 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)是一种阳性单链RNA病毒 这是2019年12月在武汉首次隔离的中国。SARS-CoV-2是冠状病毒病的起因 2019年(新冠肺炎)，现在是一种大流行，已导致130多万确诊病例和72,000例 死亡，估计病死率为4%，老年人或 免疫功能受损。几乎所有国家和地区都报告了病例，中国出现了重大疫情， 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源头，大多数 可能是蝙蝠，与最初的SARS冠状病毒约75%相同。大多数病例是通过人与人之间的直接传播 人类传播，描述了在无症状个体中的社区传播。目前，没有 反措施被授权给人类使用。开发、表征并最终部署 以抗体为基础的SARS-CoV-2治疗可以防止大量的发病率和死亡率，以及 可能会减缓它的疫情传播。这一交互式多PI计划利用了以下方面的互补专业知识 钻石、克劳和巴里克实验室将迅速开发高度中和和治疗人类 立即用于人类的抗SARS-CoV-2的单抗。为了实现这一目标，我们将 从多个恢复期获得的抗SARS-CoV-2人源单抗的制备和鉴定 研究对象。我们将确定有效的中和单抗，并通过选择自然发生的单抗来优化它们的亲和力 通过谱系测序、同胞分析和Fc效应器功能鉴定体细胞变异。保护性的 头号候选冠状病毒单抗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ACE2受体(HACE2)的人。定义…的关联性 保护，我们将使用嵌合病毒，鸟枪诱变，和中和逃逸来鉴定表位 我们最具防护性的单抗。我们的团队在生成、角色塑造和 抗体、冠状病毒生物学、疾病和保护的动物模型的优化。一种由以下成分组成的疗法 一到三个高度中和的单抗可能会立即提供对抗大流行蔓延的对策。 并帮助建立结构和功能体液保护的相关性，最终 为疫苗工作提供信息。

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.