Abstact

Influenza virus cross-subtype antibodies targeting epitopes in the hemagglutinin (HA) head are rare because these epitopes are variable between influenza virus subtypes. We found that a large proportion of monoclonal antibodies (mAbs) isolated from individuals immunized with the 2021-22 seasonal influenza vaccine bound to an epitope on the HA head of both the H1N1 vaccine strain and H3N2 strains from the mid-1990s. The unmutated common ancestors of many of these mAbs reacted to both the 1990s H3s and the 2021-22 H1 vaccine strain. These cross-subtype antibodies were also found in polyclonal sera, but only among individuals born in the 1990s. Ferrets sequentially exposed to a 1990s H3N2 virus and contemporary influenza vaccine also produced H1/H3 cross-reactive antibodies. Recently, H1N1 viruses have acquired a substitution that abrogates the binding of these antibodies. Together, our study demonstrates how prior influenza virus exposures can influence the specificity of antibodies elicited by entirely different influenza virus subtypes.