Abstract
Traditional influenza vaccines primarily induce a narrow antibody response that offers no protection against heterosubtypic infections. Murine studies have shown that T cells can protect against a broad range of influenza strains. However, ferrets are a more potent model for studying immune correlates of protection in influenza infection. We therefore set out to investigate the role of systemic and respiratory T cells in the protection against heterosubtypic influenza A infections in ferrets. H1N1-priming induced systemic and respiratory T cells that responded against pandemic H2N2 and correlated with reduced viral replication and disease. CD8-positive T cell responses in the upper and lower respiratory tract were exceptionally high. We additionally confirmed that H2N2-responsive T cells are present in healthy human blood donors. These findings underline the importance of the T cell response in influenza immunity and show that T cells are a potent target for future universal influenza vaccines.