Identification of a cross-neutralizing antibody that targets the receptor binding site of H1N1 and H5N1 influenza viruses

Influenza A viruses pose a significant threat globally each year, underscoring the need for a vaccine- or antiviral-based broad-protection strategy. Here, we describe a chimeric monoclonal antibody, C12H5, that offers neutralization against seasonal and pandemic H1N1 viruses, and cross-protection against some H5N1 viruses. Notably, C12H5 mAb offers broad neutralizing activity against H1N1 and H5N1 viruses by controlling virus entry and egress, and offers protection against H1N1 and H5N1 viral challenge in vivo. Through structural analyses, we show that C12H5 engages hemagglutinin (HA) at a distinct epitope overlapping the receptor binding site and covering the 140-loop. We identified eight highly conserved (>−90%) residues essential for broad H1N1 recognition, with tolerance for Asp or Glu at position 190, a molecular determinant for human or avian host-specific recognition, enabling cross-neutralization. These results could benefit antiviral drug development and broad-protection influenza vaccine design.