A potent neutralizing site III-specific human antibody neutralizes human metapneumovirus .

Human metapneumovirus (hMPV) is a leading cause of viral lower respiratory tract infection in children. The sole target of neutralizing antibodies targeting hMPV is the fusion (F) protein， a class I viral fusion protein mediating virus-cell membrane fusion. There have been several monoclonal antibodies (mAbs) isolated that neutralize hMPV， however， determining the antigenic sites on the hMPV F protein mediating such neutralizing antibody generation would assist efforts for effective vaccine design. In this report， the isolation and characterization of four new human mAbs is described， termed MPV196， MPV201， MPV314， and MPV364. Among the four mAbs， MPV364 was found to be the most potent neutralizing mAb Binding studies to monomeric and trimeric hMPV F revealed that MPV364 had the weakest binding affinity to monomeric hMPV F as compared to the other three mAbs， yet binding experiments to trimeric hMPV F showed limited difference in binding affinity， suggesting MPV364 targets an antigenic site incorporating two protomers. Epitope binning studies showed that MPV364 targets antigenic site III on the hMPV F protein and competes for binding with previously discovered mAbs MPE8 and 25P13， which both cross-react with the respiratory syncytial virus (RSV) F protein. However， MPV364 does not cross-react with the RSV F protein， and the competition profile suggests it binds to the hMPV F protein in a binding pose slightly shifted from mAbs MPE8 and 25P13. MPV364 was further assessed and was shown to substantially reduce viral replication in the lungs of BALB/c mice. Overall， these data reveal a new binding region near antigenic site III of the hMPV F protein that elicits potent neutralizing hMPV F-specific mAbs， and provide a new panel of neutralizing mAbs that are candidates for therapeutic development. Recent progress in understanding the human immune response to respiratory syncytial virus has paved the way for new vaccine antigens and therapeutics to prevent and treat disease. Progress toward understanding the immune response to human metapneumovirus (hMPV) has lagged behind， although hMPV is a leading cause of lower respiratory tract infection in children. In this report， we advanced the field by isolating a panel of human mAbs to the hMPV F protein. One potent neutralizing mAb， MPV364， targets antigenic site III on the hMPV F protein and incorporates two protomers into its epitope， yet is unique from previously discovered site III-mAbs as it does not cross-react with the RSV F protein. We further examined MPV364 ， and found it limits viral replication in BALB/c mice. Altogether， these data provide new mAb candidates for therapeutic development， and provide insights into hMPV vaccine development.