The SARS-CoV-2 Omicron variant has very high levels of transmission, is resistant to neutralization by authorized therapeutic human monoclonal antibodies (mAb) and is less sensitive to vaccine-mediated immunity. To provide additional therapies against Omicron, we isolated a mAb named P2G3 from a previously infected vaccinated donor and showed that it has picomolar-range neutralizing activity against Omicron BA.1, BA.1.1, BA.2 and all other variants tested. We solved the structure of P2G3 Fab in complex with the Omicron spike using cryo-electron microscopy at 3.04 Å resolution to identify the P2G3 epitope as a Class 3 mAb that is different from mAb-binding spike epitopes reported previously. Using a SARS-CoV-2 Omicron monkey challenge model, we show that P2G3 alone, or in combination with P5C3 (a broadly active Class 1 mAb previously identified), confers complete prophylactic or therapeutic protection. Although we could select for SARS-CoV-2 mutants escaping neutralization by P2G3 or by P5C3 in vitro, they had low infectivity and ‘escape’ mutations are extremely rare in public sequence databases. We conclude that this combination of mAbs has potential as an anti-Omicron drug.

SARS-CoV-2 Omicron 变体具有非常高的传播水平，对经授权的治疗性人单克隆抗体 (mAb) 的中和具有抵抗力，并且对疫苗介导的免疫不太敏感。为了提供针对 Omicron 的额外疗法，我们从先前感染的接种疫苗供体中分离出一种名为 P2G3 的 mAb，并表明它对 Omicron BA.1、BA.1.1、BA.2 和所有其他测试的变体具有皮摩尔范围的中和活性。我们使用低温电子显微镜以 3.04 Å 分辨率解析了与 Omicron 尖峰复合物的 P2G3 Fab 结构，以将 P2G3 表位鉴定为不同于之前报道的 mAb 结合尖峰表位的 3 类 mAb。使用 SARS-CoV-2 Omicron 猴子挑战模型，我们显示 P2G3 单独或与 P5C3（先前确定的广泛活性 1 类 mAb）结合使用，提供完整的预防或治疗保护。尽管我们可以在体外选择逃脱 P2G3 或 P5C3 中和的 SARS-CoV-2 突变体，但它们的传染性低，并且“逃脱”突变在公共序列数据库中极为罕见。我们得出结论，这种 mAb 组合具有作为抗 Omicron 药物的潜力。