Control of the ongoing SARS-CoV-2 pandemic is endangered by the emergence of viral variants with increased transmission efficiency, resistance to marketed therapeutic antibodies, and reduced sensitivity to vaccine-induced immunity. Here, we screen B cells from COVID-19 donors and identify P5C3, a highly potent and broadly neutralizing monoclonal antibody with picomolar neutralizing activity against all SARS-CoV-2 variants of concern (VOCs) identified to date. Structural characterization of P5C3 Fab in complex with the spike demonstrates a neutralizing activity defined by a large buried surface area, highly overlapping with the receptor-binding domain (RBD) surface necessary for ACE2 interaction. We further demonstrate that P5C3 shows complete prophylactic protection in the SARS-CoV-2-infected hamster challenge model. These results indicate that P5C3 opens exciting perspectives either as a prophylactic agent in immunocompromised individuals with poor response to vaccination or as combination therapy in SARS-CoV-2-infected individuals.

由于病毒变种的传播效率提高、对市售治疗性抗体具有抵抗力以及对疫苗诱导免疫的敏感性降低，对正在进行的 SARS-CoV-2 大流行的控制受到威胁。在这里，我们筛选了来自 COVID-19 供体的 B 细胞，并鉴定了 P5C3，这是一种高效且广泛中和的单克隆抗体，对迄今为止发现的所有 SARS-CoV-2 相关变体 (VOC) 具有皮摩尔中和活性。与刺突复合物中的 P5C3 Fab 的结构表征表明，中和活性由大的埋藏表面积定义，与 ACE2 相互作用所需的受体结合域 (RBD) 表面高度重叠。我们进一步证明 P5C3 在 SARS-CoV-2 感染的仓鼠攻击模型中显示出完整的预防性保护。这些结果表明，P5C3 开启了令人兴奋的前景，无论是作为对疫苗接种反应不佳的免疫功能低下个体的预防剂，还是作为 SARS-CoV-2 感染个体的联合疗法。