Heterosubtypic Protections against Human-Infecting Avian Influenza Viruses Correlate to Biased Cross-T-Cell Responses

Zhao, Min; Liu, Kefang; Luo, Jiejian; Tan, Shuguang; Quan, Chuansong; Zhang, Shuijun; Chai, Yan; Qi, Jianxun; Li, Yan; Bi, Yuhai; Xiao, Haixia; Wong, Gary; Zhou, Jianfang; Jiang, Taijiao; Liu, Wenjun; Yu, Hongjie; Yan, Jinghua; Liu, Yingxia; Shu, Yuelong; Wu, Guizhen; Wu, Aiping; Gao, George F.; Liu, William J.

Against a backdrop of seasonal influenza virus epidemics, emerging avian influenza viruses (AIVs) occasionally jump from birds to humans, posing a public health risk, especially with the recent sharp increase in H7N9 infections. Evaluations of cross-reactive T-cell immunity to seasonal influenza viruses and human-infecting AIVs have been reported previously. However, the roles of influenza A virus-derived epitopes in the cross-reactive T-cell responses and heterosubtypic protections are not well understood; understanding those roles is important for preventing and controlling new emerging AIVs. Here, among the members of a healthy population presumed to have previously been infected by pandemic H1N1 (pH1N1), we found that pH1N1-specific T cells showed cross- but biased reactivity to human-infecting AIVs, i.e., H5N1, H6N1, H7N9, and H9N2, which correlates with distinct protections. Through a T-cell epitope-based phylogenetic analysis, the cellular immunogenic clustering expanded the relevant conclusions to a broader range of virus strains. We defined the potential key conserved epitopes required for cross-protection and revealed the molecular basis for the immunogenic variations. Our study elucidated an overall profile of cross-reactivity to AIVs and provided useful recommendations for broad-spectrum vaccine development.