Characterization of prefusion-F-specific antibodies elicited by natural infection with human metapneumovirus

Abstract

Human metapneumovirus (hMPV) is a major cause of acute respiratory tract infections in infants and the elderly for which there are no approved vaccines or antibody therapies. The viral fusion (F) glycoprotein is required for entry and is the primary target of neutralizing antibodies, however, little is known about the humoral immune response generated by humans as a result of natural infection. Here, we use stabilized hMPV F proteins to interrogate memory B cells from two elderly donors. We obtained over 700 paired non-IgM antibody sequences representing 563 clonotypes, indicative of a highly polyclonal antibody response to hMPV F in these individuals. Characterization of 136 of these monoclonal antibodies revealed broad recognition of the hMPV F surface, with potent neutralizing antibodies targeting each antigenic site. Cryo-EM structures of two neutralizing antibodies reveal the molecular basis for recognition of two prefusion-specific epitopes at the membrane-distal apex of hMPV F. Collectively these results provide new insights into the humoral response to hMPV infection in the elderly and will guide development of novel vaccine antigens.