Most human monoclonal antibodies (mAbs) neutralizing SARS-CoV-2 recognize the spike (S) protein receptor-binding domain and block virus interactions with the cellular receptor angiotensin-converting enzyme 2. We describe a panel of human mAbs binding to diverse epitopes on the N-terminal domain (NTD) of S protein from SARS-CoV-2 convalescent donors and found a minority of these possessed neutralizing activity. Two mAbs (COV2-2676 and COV2-2489) inhibited infection of authentic SARS-CoV-2 and recombinant VSV/SARS-CoV-2 viruses. We mapped their binding epitopes by alanine-scanning mutagenesis and selection of functional SARS-CoV-2 S neutralization escape variants. Mechanistic studies showed that these antibodies neutralize in part by inhibiting a post-attachment step in the infection cycle. COV2-2676 and COV2-2489 offered protection either as prophylaxis or therapy, and Fc effector functions were required for optimal protection. Thus, natural infection induces a subset of potent NTD-specific mAbs that leverage neutralizing and Fc-mediated activities to protect against SARS-CoV-2 infection using multiple functional attributes.

中文翻译：

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识别SARS-CoV-2刺突蛋白N末端结构域的中和和保护性人类单克隆抗体

大多数中和SARS-CoV-2的人类单克隆抗体（mAbs）均能识别刺突（S）蛋白受体结合域，并阻断病毒与细胞受体血管紧张素转化酶2的相互作用。 SARS-CoV-2恢复期供体的S蛋白的N末端结构域（NTD），发现其中的少数具有中和活性。两个单克隆抗体（COV2-2676和COV2-2489）抑制了真实SARS-CoV-2和重组VSV / SARS-CoV-2病毒的感染。我们通过丙氨酸扫描诱变和功能性SARS-CoV-2 S中和逃逸变体的选择来绘制它们的结合表位。机理研究表明，这些抗体通过抑制感染周期中的附着后步骤而部分中和。COV2-2676和COV2-2489提供预防或治疗方面的保护，并且需要Fc效应子功能才能获得最佳保护。因此，自然感染诱导了有效的NTD特异性mAb的子集，该子集利用中和和Fc介导的活性使用多种功能属性来防御SARS-CoV-2感染。