Immune history confers antibody- and T cell-dependent cross-protection against highly pathogenic avian influenza H5N1 viruses

Abstract

The rapid spread of highly pathogenic avian H5 influenza (HPAI) clade 2.3.4.4b in U.S. cattle represents an urgent and evolving public health threat. Our findings reveal that pre-existing immunity, whether from seasonal H1N1 infection or live-attenuated vaccination, can confer substantial protection against lethal bovine- and feline-derived HPAI H5N1 viruses, even in the absence of strong cross-neutralizing antibody titers. By integrating T cell epitope mapping with mechanistic depletion studies, we demonstrate that conserved CD4 and CD8 T cell epitopes across H1N1 and H5N1 strains underpin this cross-protection. Critically, loss of CD4 T cell help during primary H1N1 infection disrupts the development of cross-reactive antibody responses and markedly worsens outcomes after H5N1 challenge. These results identify memory T cell responses as important determinants of heterosubtypic immunity and highlight the need to incorporate T cell-focused metrics into risk assessment, vaccine evaluation, and preparedness strategies for emerging HPAI H5N1 viruses.