SARS-CoV-2 Omicron variant has presented significant challenges to current antibodies and vaccines. Herein, we systematically compared the efficacy of 50 human monoclonal antibodies (mAbs), covering the seven identified epitope classes of the SARS-CoV-2 RBD, against Omicron sub-variants BA.1, BA.1.1, BA.2, and BA.3. Binding and pseudovirus-based neutralizing assays revealed that 37 of the 50 mAbs lost neutralizing activities, whereas the others displayed variably decreased activities against the four Omicron sub-variants. BA.2 was found to be more sensitive to RBD-5 antibodies than the other sub-variants. Furthermore, a quaternary complex structure of BA.1 RBD with three mAbs showing different neutralizing potencies against Omicron provided a basis for understanding the immune evasion of Omicron sub-variants and revealed the lack of G446S mutation accounting for the sensitivity of BA.2 to RBD-5 mAbs. Our results may guide the application of the available mAbs and facilitate the development of universal therapeutic antibodies and vaccines against COVID-19.

SARS-CoV-2 Omicron 变体对当前的抗体和疫苗提出了重大挑战。在此，我们系统地比较了 50 种人类单克隆抗体 (mAb) 的功效，涵盖 SARS-CoV-2 RBD 的七个已识别表位类别，针对 Omicron 亚变体 BA.1、BA.1.1、BA.2 和 BA .3. 结合和基于假病毒的中和分析表明，50 种 mAb 中有 37 种失去了中和活性，而其他的则显示出针对四种 Omicron 亚变体的活性有所下降。发现 BA.2 比其他亚变体对 RBD-5 抗体更敏感。此外，BA的四元复杂结构。1 具有三种 mAb 的 RBD 显示出针对 Omicron 的不同中和效力，为理解 Omicron 亚变体的免疫逃避提供了基础，并揭示了缺乏 G446S 突变导致 BA.2 对 RBD-5 mAb 的敏感性。我们的结果可能会指导可用单克隆抗体的应用，并促进针对 COVID-19 的通用治疗性抗体和疫苗的开发。