Structural characterization of M8C10, a neutralizing antibody targeting a highly conserved prefusion-specific epitope on the metapneumovirus fusion trimerization interface

Human metapneumovirus (hMPV) is a major respiratory pathogen worldwide. Here, we report the crystal structure of a neutralizing antibody M8C10 isolated from human B cells that targets the viral fusion protein (hMPV-F) trimerization interface. This is a novel prefusion-specific epitope that is highly conserved across hMPV strains and other related viruses. The interactions between M8C10 and hMPV-F are largely driven by residues on the light chain with most hypermutated light chain residues on or near the interface. This highlights the immune recognition of a buried trimerization interface during the in vivo affinity maturation process. In addition, in vivo cotton rat challenge studies were performed that show M8C10 provides strong lung protection against hMPV A viral challenge. The hMPV-F:M8C10 Fab structure reported reveals a class of hMPV antibodies in the human immune repertoire with a novel neutralization mechanism, targeting the trimerization interface of hMPV-F antigen.IMPORTANCEHuman metapneumovirus (hMPV) is a common pathogen causing lower respiratory tract infections worldwide and can develop severe symptoms in high-risk populations such as infants, the elderly, and immunocompromised patients. There are no approved hMPV vaccines or neutralizing antibodies available for therapeutic or prophylactic use. The trimeric hMPV fusion F protein is the major target of neutralizing antibodies in human sera. Understanding the immune recognition of antibodies to hMPV-F antigen will provide critical insights into developing efficacious hMPV monoclonal antibodies and vaccines. Human metapneumovirus (hMPV) is a common pathogen causing lower respiratory tract infections worldwide and can develop severe symptoms in high-risk populations such as infants, the elderly, and immunocompromised patients. There are no approved hMPV vaccines or neutralizing antibodies available for therapeutic or prophylactic use. The trimeric hMPV fusion F protein is the major target of neutralizing antibodies in human sera. Understanding the immune recognition of antibodies to hMPV-F antigen will provide critical insights into developing efficacious hMPV monoclonal antibodies and vaccines.