Center for Vaccines and Immunology, College of Veterinary Medicine, University of Georgia, Athens, GA 30602.
Department of Infectious Diseases, College of Veterinary Medicine, University of Georgia, Athens, GA 30602.
Proc Natl Acad Sci U S A. 2022 Jun 21;119(25):e2203326119. doi: 10.1073/pnas.2203326119. Epub 2022 Jun 13.
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.
人偏肺病毒（hMPV）是导致全球儿童发病和住院的主要原因，但目前尚无针对 hMPV 疾病预防和治疗的疫苗或疗法。hMPV 融合（F）蛋白是中和抗体的唯一靶标。为了绘制 hMPV F 蛋白上的免疫优势表位图谱，我们分离了一组人源单克隆抗体（mAbs），并评估了 mAbs 的结合亲和力、中和效力和表位特异性。我们发现大多数 mAbs 针对 hMPV F 蛋白上的不同表位，并且我们发现针对抗原性位点 III 有多种 mAb 结合方法。最有效的 mAb 是 MPV467，其效力为皮摩尔级，在预防性和治疗性小鼠挑战研究中进行了检查，并且当在病毒感染前 24 小时或感染后 72 小时给予时，MPV467 限制了小鼠肺部的病毒复制。我们使用冷冻电子显微镜将 MPV467 与 hMPV F 蛋白的复合物解析至 3.3 Å 的分辨率，揭示了一个重叠单个原体上抗原性位点 II 和 V 的新颖的预融合特异性表位复合物。总体而言，我们的数据揭示了 hMPV F 蛋白上免疫优势抗原表位的见解，确定了针对 hMPV F 疾病预防和治疗的 mAb 疗法，并提供了 hMPV F 蛋白上的预融合特异性表位的发现。
