Abstract
Overcoming interfering impacts of pre-existing immunity to generate universally protective influenza A virus (IAV)-specific T cell immunity through vaccination is a high priority. In this study, we passively transfer varied amounts of H1N1-IAV-specific immune serum before H1N1-IAV infection to determine how different levels of pre-existing Ab influence the generation and protective potential of heterosubtypic T cell responses in a murine model. Surprisingly, IAV nucleoprotein-specific CD4 and CD8 T cell responses are readily detected in infected recipients of IAV-specific immune serum regardless of the amount transferred. When compared with responses in control groups and recipients of low and intermediate levels of convalescent serum, nucleoprotein-specific T cell responses in recipients of high levels of IAV-specific serum, which prevent overt weight loss and reduce peak viral titers in the lungs, are, however, markedly reduced. Although detectable at priming, this response recalls poorly and is unable to mediate protection against a lethal heterotypic (H3N2) virus challenge at later memory time points. A similar failure to generate protective heterosubtypic T cell immunity during IAV priming is seen in offspring of IAV-primed mothers that naturally receive high titers of IAV-specific Ab through maternal transfer. Our findings support that priming of protective heterosubtypic T cell responses can occur in the presence of intermediate levels of pre-existing Ab. These results have high relevance to vaccine approaches aiming to incorporate and evaluate cellular and humoral immunity towards IAV and other viral pathogens against which T cells can protect against variants escaping Ab-mediated protection.