Rappazzo, C GarrettHsieh, Ching-LinRush, Scott AEsterman, Emma SDelgado-Romero, TeresaGeoghegan, James CWec, Anna ZSakharkar, MrunalMas-Lloret, VicenteMcLellan, Jason SWalker, Laura M2023-05-092023-05-092022-09-13Immunity. 2022 Sep 13;55(9):1710-1724.e8.http://hdl.handle.net/20.500.12105/16032Human 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.engVoRhttp://creativecommons.org/licenses/by-nc-nd/4.0/Antibodies, NeutralizingAntibodies, ViralMetapneumovirusRespiratory Tract InfectionsAgedAnimalsEpitopesGlycoproteinsHumansViral Fusion ProteinsYoung AdultAttribution-NonCommercial-NoDerivatives 4.0 Internacional359445295591710-1724.e810.1016/j.immuni.2022.07.0031097-4180Immunityopen access