Understanding the molecular features of neutralizing epitopes is important for developing vaccines/therapeutics against emerging SARS-CoV-2 variants. We describe three monoclonal antibodies (mAbs) generated from COVID-19 recovered individuals during the first wave of the pandemic in India. These mAbs had publicly shared near germline gene usage and potently neutralized Alpha and Delta, poorly neutralized Beta, and failed to neutralize Omicron BA.1 SARS-CoV-2 variants. Structural analysis of these mAbs in complex with trimeric spike protein showed that all three mAbs bivalently bind spike with two mAbs targeting class 1 and one targeting a class 4 receptor binding domain epitope. The immunogenetic makeup, structure, and function of these mAbs revealed specific molecular interactions associated with the potent multi-variant binding/neutralization efficacy. This knowledge shows how mutational combinations can affect the binding or neutralization of an antibody, which in turn relates to the efficacy of immune responses to emerging SARS-CoV-2 escape variants.

了解中和表位的分子特征对于开发针对新出现的 SARS-CoV-2 变体的疫苗/疗法非常重要。我们描述了印度第一波大流行期间 COVID-19 康复者产生的三种单克隆抗体 (mAb)。这些单克隆抗体公开分享了近种系基因的使用，并有效中和 Alpha 和 Delta，中和 Beta 效果较差，但未能中和 Omicron BA.1 SARS-CoV-2 变体。对这些 mAb 与三聚刺突蛋白复合物的结构分析表明，所有三种 mAb 都与刺突蛋白二价结合，其中两种 mAb 靶向 1 类受体，另一种 mAb 靶向 4 类受体结合域表位。这些单克隆抗体的免疫遗传学组成、结构和功能揭示了与有效的多变体结合/中和功效相关的特定分子相互作用。这些知识表明突变组合如何影响抗体的结合或中和，这反过来又与对新出现的 SARS-CoV-2 逃逸变体的免疫反应的功效相关。