Human metapneumovirus (hMPV) is a leading cause of morbidity and hospitalization among children worldwide, however, no vaccines or therapeutics are currently available for hMPV disease prevention and treatment. The hMPV fusion (F) protein is the sole target of neutralizing antibodies. To map the immunodominant epitopes on the hMPV F protein, we isolated a panel of human monoclonal antibodies (mAbs), and the mAbs were assessed for binding avidity, neutralization potency, and epitope specificity. We found the majority of the mAbs target diverse epitopes on the hMPV F protein, and we discovered multiple mAb binding approaches for antigenic site III. The most potent mAb, MPV467, which had picomolar potency, was examined in prophylactic and therapeutic mouse challenge studies, and MPV467 limited virus replication in mouse lungs when administered 24 h before or 72 h after viral infection. We determined the structure of MPV467 in complex with the hMPV F protein using cryo-electron microscopy to a resolution of 3.3 Å, which revealed a complex novel prefusion-specific epitope overlapping antigenic sites II and V on a single protomer. Overall, our data reveal insights into the immunodominant antigenic epitopes on the hMPV F protein, identify a mAb therapy for hMPV F disease prevention and treatment, and provide the discovery of a prefusion-specific epitope on the hMPV F protein.

中文翻译：

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超强抗体介导的人间质肺病毒中和的结构基础。


人类偏肺病毒 (hMPV) 是全世界儿童发病和住院的主要原因，然而，目前尚无用于预防和治疗 hMPV 疾病的疫苗或治疗方法。 hMPV 融合 (F) 蛋白是中和抗体的唯一目标。为了绘制 hMPV F 蛋白上的免疫显性表位，我们分离了一组人单克隆抗体 (mAb)，并对 mAb 的结合亲和力、中和效力和表位特异性进行了评估。我们发现大多数 mAb 靶向 hMPV F 蛋白上的不同表位，并且我们发现了针对抗原位点 III 的多种 mAb 结合方法。最有效的单克隆抗体 MPV467 具有皮摩尔效力，在预防性和治疗性小鼠攻击研究中进行了检查，在病毒感染前 24 小时或感染后 72 小时施用 MPV467 可以限制小鼠肺部的病毒复制。我们使用冷冻电子显微镜以 3.3 Å 的分辨率确定了 MPV467 与 hMPV F 蛋白复合物的结构，这揭示了单个原聚体上与抗原位点 II 和 V 重叠的复杂的新型融合前特异性表位。总体而言，我们的数据揭示了对 hMPV F 蛋白上的免疫显性抗原表位的见解，确定了用于 hMPV F 疾病预防和治疗的单克隆抗体疗法，并发现了 hMPV F 蛋白上的融合前特异性表位。