Convergent antigenic drift of the influenza hemagglutinin lateral patch across time and species.

The lateral patch epitope of the H1 hemagglutinin (HA) was a dominant target of antibodies following exposure to the 2009 pandemic H1N1 virus. However, the conservation and potential for antigenic drift in the lateral patch remain unresolved. Here, we used lateral patch-specific monoclonal antibodies (mAbs) to understand the antigenicity of the lateral patch of human, avian, and swine H1Nx viruses spanning from 1918 to 2022. We identified discrete mutations that evaded lateral patch-targeting mAbs in pre- and post-2009 H1N1 viruses, leading to genetic differences in lateral patch-targeting antibodies in individuals across birth years. We observed that the lateral patch remains well conserved across zoonotic sources, suggesting existing lateral patch antibodies could protect against a future H1Nx pandemic. Together, these data support that lateral patch antigenic drift has shaped the human B cell repertoire against influenza viruses and that the lateral patch remains an attractive target for pandemic preparedness.