This research paper describes a chimeric monoclonal antibody, C12H5, which neutralizes seasonal and pandemic H1N1 viruses and offers cross-protection against some H5N1 viruses. C12H5 exhibits broad neutralizing activity by controlling virus entry and egress, offering *in vivo* protection. Structural analyses reveal that C12H5 binds to hemagglutinin (HA) at an epitope overlapping the receptor-binding site (RBS) and covering the 140-loop. Eight highly conserved residues crucial for broad H1N1 recognition were identified, and the antibody’s tolerance for Asp or Glu at position 190 contributes to its cross-neutralization potential. These results may aid in the development of antiviral drugs and broad-protection influenza vaccines.
