Human metapneumovirus (hMPV) is a leading cause of acute lower respiratory tract infections in high-risk populations, yet there are no vaccines or anti-viral therapies approved for the prevention or treatment of hMPV-associated disease. Here, we used a high-throughput single-cell technology to interrogate memory B cell responses to the hMPV fusion (F) glycoprotein in young adult and elderly donors. Across all donors, the neutralizing antibody response was primarily directed to epitopes expressed on both pre- and post-fusion F conformations. However, we identified rare, highly potent broadly neutralizing antibodies that recognize pre-fusion-specific epitopes and structurally characterized an antibody that targets a site of vulnerability at the pre-fusion F trimer apex. Additionally, monotherapy with neutralizing antibodies targeting three distinct antigenic sites provided robust protection against lower respiratory tract infection in a small animal model. This study provides promising monoclonal antibody candidates for passive immunoprophylaxis and informs the rational design of hMPV vaccine immunogens.

人偏肺病毒 (hMPV) 是高危人群急性下呼吸道感染的主要原因，但目前还没有批准用于预防或治疗 hMPV 相关疾病的疫苗或抗病毒疗法。在这里，我们使用高通量单细胞技术来询问年轻成人和老年供体中记忆 B 细胞对 hMPV 融合 (F) 糖蛋白的反应。在所有供体中，中和抗体反应主要针对在融合前和融合后 F 构象上表达的表位。然而，我们发现了罕见的、高效的广泛中和抗体，这些抗体识别融合前特异性表位，并在结构上表征了一种针对融合前 F 三聚体顶点易损位点的抗体。此外，靶向三个不同抗原位点的中和抗体的单一疗法在小动物模型中提供了针对下呼吸道感染的强大保护。该研究为被动免疫预防提供了有希望的单克隆抗体候选物，并为hMPV疫苗免疫原的合理设计提供了信息。