Background.?The emergence of infections by the novel avian influenza A (H7N9) virus has posed a threat to human health. Cross-immunity between H7N9 and other heterosubtypic influenza viruses affected by antigenicity-dependent substitutions needs to be investigated.

Methods.?We investigated the cellular and humoral immune responses against H7N9 and the 2009 pandemic H1N1 influenza viruses, by serological and T-cell-specific assays in a healthy population. The molecular bases of the cellular and humoral antigenic variability of H7N9 were illuminated by structural determination.

Results.?We not only found antibodies against H7N9 were lacking in the studied population, but also revealed both CD4⁺ and CD8⁺ T-cells that cross-reacted with H7N9 were at significantly lower levels than those against the 2009pH1N1 peptides with substitutions. Moreover, individual peptides for the H7N9 virus with low cross-reactivity were identified. Structural determination indicated that substitutions within these peptides influence the antigenic variability of H7N9 through both major histocompatibility complex (MHC)-binding and T-cell receptor (TCR)-docking.

Conclusions.?The impact of antigenicity-dependent substitutions on cross-reactivity of T-cell immunity against the novel H7N9 virus in the healthy population benefits the understanding of immune evasion of influenza viruses and provides a useful reference for universal vaccine development.