The COVID-19 pandemic is a major threat to global health for which there are only limited medical countermeasures, and we lack a thorough understanding of mechanisms of humoral immunity. From a panel of monoclonal antibodies (mAbs) targeting the spike (S) glycoprotein isolated from the B cells of infected subjects, we identified several mAbs that exhibited potent neutralizing activity with IC50 values as low as 0.9 or 15 ng/mL in pseudovirus or wild-type (wt) SARS-CoV-2 neutralization tests, respectively. The most potent mAbs fully block the receptor-binding domain of S (SRBD) from interacting with human ACE2. Competition-binding, structural, and functional studies allowed clustering of the mAbs into defined classes recognizing distinct epitopes within major antigenic sites on the SRBD. Electron microscopy studies revealed that these mAbs recognize distinct conformational states of trimeric S protein. Potent neutralizing mAbs recognizing unique sites, COV2-2196 and COV2-2130, bound simultaneously to S and synergistically neutralized authentic SARS-CoV-2 virus. In two murine models of SARS-CoV-2 infection, passive transfer of either COV2-2916 or COV2-2130 alone or a combination of both mAbs protected mice from severe weight loss and reduced viral burden and inflammation in the lung. These results identify protective epitopes on the SRBD and provide a structure-based framework for rational vaccine design and the selection of robust immunotherapeutic cocktails.

中文翻译：

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强效中和人抗体，可阻断SARS-CoV-2受体结合并保护动物。

COVID-19大流行是对全球健康的主要威胁，为此，医学对策十分有限，我们对体液免疫机制缺乏透彻的了解。从针对从感染对象B细胞中分离出的尖峰（S）糖蛋白的单克隆抗体（mAb）组中，我们鉴定了几种在假病毒或野生型中表现出强力中和活性且IC50值低至0.9或15 ng / mL的mAb型（wt）SARS-CoV-2中和测试。最有效的单克隆抗体完全阻断S的受体结合域（SRBD）与人ACE2的相互作用。竞争结合，结构和功能研究允许将mAb聚类为确定的类别，从而识别SRBD主要抗原位点内的不同表位。电子显微镜研究表明，这些单克隆抗体识别三聚体S蛋白的不同构象状态。识别独特位点的有效中和单克隆抗体COV2-2196和COV2-2130同时与S结合并协同中和正宗的SARS-CoV-2病毒。在SARS-CoV-2感染的两个鼠模型中，单独COV2-2916或COV2-2130或两种mAb组合的被动转移可保护小鼠免受严重的体重减轻和病毒载量减少以及肺部炎症的影响。这些结果确定了SRBD上的保护性表位，并为合理的疫苗设计和强大的免疫治疗混合物的选择提供了基于结构的框架。同时结合到S和协同中和的真实SARS-CoV-2病毒。在SARS-CoV-2感染的两个鼠模型中，单独COV2-2916或COV2-2130或两种mAb组合的被动转移可保护小鼠免受严重的体重减轻和病毒载量减少以及肺部炎症的影响。这些结果确定了SRBD上的保护性表位，并为合理的疫苗设计和强大的免疫治疗混合物的选择提供了基于结构的框架。同时结合到S和协同中和的真实SARS-CoV-2病毒。在SARS-CoV-2感染的两个鼠模型中，单独COV2-2916或COV2-2130或两种mAb组合的被动转移可保护小鼠免受严重的体重减轻和病毒载量减少以及肺部炎症的影响。这些结果确定了SRBD上的保护性表位，并为合理的疫苗设计和强大的免疫治疗混合物的选择提供了基于结构的框架。