The worldwide spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has led to the repeated emergence of variants of concern. For the Omicron variant, sub-lineages BA.1 and BA.2, respectively, contain 33 and 29 nonsynonymous and indel spike protein mutations. These amino acid substitutions and indels are implicated in increased transmissibility and enhanced immune evasion. By reverting individual spike mutations of BA.1 or BA.2, we characterize the molecular effects of the Omicron spike mutations on expression, ACE2 receptor affinity, and neutralizing antibody recognition. We identified key mutations enabling escape from neutralizing antibodies at a variety of epitopes. Stabilizing mutations in the N-terminal and S2 domains of the spike protein can compensate for destabilizing mutations in the receptor binding domain, enabling the record number of mutations in Omicron. Our results provide a comprehensive account of the mutational effects in the Omicron spike protein and illustrate previously uncharacterized mechanisms of host evasion.

严重急性呼吸系统综合症冠状病毒 2 (SARS-CoV-2) 在世界范围内的传播导致了令人担忧的变体的反复出现。对于 Omicron 变体，亚谱系 BA.1 和 BA.2 分别包含 33 和 29 个非同义和插入缺失刺突蛋白突变。这些氨基酸取代和插入缺失与提高的传播性和增强的免疫逃避有关。通过恢复 BA.1 或 BA.2 的单个尖峰突变，我们描述了 Omicron 尖峰突变对表达、ACE2 受体亲和力和中和抗体识别的分子效应。我们确定了能够逃避各种表位中和抗体的关键突变。刺突蛋白 N 端和 S2 域的稳定突变可以补偿受体结合域的不稳定突变，在 Omicron 中实现创纪录的突变数量。我们的结果全面说明了 Omicron 刺突蛋白的突变效应，并说明了以前未表征的宿主逃避机制。