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Abstract
Human metapneumovirus (hMPV) is a significant cause of acute respiratory illness in human, with the majority of children being seropositive for hMPV by five years of age. Infants, the elderly population, and immunocompromised patients are more susceptible to severe hMPV infections that lead to hospitalization and death. The fusion (F) protein is the only target of neutralizing antibodies against hMPV. However, our knowledge of the immunological properties of hMPV F is still limited, and currently there are no vaccines or antibody-based treatments against hMPV. In this study, we determined the crystal structures of genotype B hMPV F in both pre-fusion and post-fusion conformations, confirmed the binding of hMPV F to a potential host receptor, heparan sulfate. Through hybridoma fusion and antigen-specific flow sorting, we identified 20 hMPV F-specific mAbs from human PBMCs. Epitope binning data showed these mAbs bind to different epitopes on hMPV F and two novel epitopes were characterized by crystallography and cryo-EM. In addition, most of the mAbs can neutralize the virus and enhance Fc-dependent phagocytosis of THP-1 cells in vitro. Three mAbs were further tested as treatments in rodent hMPV infection models, and mAb MPV467 protected the mice and immunosuppressed cotton rats from hMPV infections both prophylactically and therapeutically. Based on the epitopes of pneumovirus F proteins characterized in this and previous studies, we designed a chimeric immunogen (RHMS-1) that covers the immunodominant epitopes of both hMPV F and RSV F. Vaccination of RHMS-1induced potent neutralizing antibodies and protected the mice from both hMPV and RSV challenges. Overall, our study provides novel insight on the receptor-binding properties and the antigenic sites of hMPV F, the hMPV F-specific mAbs, and the epitope-based vaccines reported in this study will be promising candidates of countermeasures against hMPV.