Immunogenicity of Teffector and Treg epitopes from H7N9 avian-origin influenza: impact of cross-reactivity with the human genome (VAC2P.934)

Avian-origin H7N9 influenza is a novel influenza A virus (IAV) that emerged in humans in China in 2013. Using immunoinformatic tools, we found this virus has lower T cell epitope content than other IAV subtypes overall, and that some epitopes bear homology to human sequences. We hypothesized that these features may make the virus poorly immunogenic. To evaluate the reactivity of H7N9 epitopes, we synthesized four sets of H7N9 sequences with the following features: (i) unique to H7N9, (ii) cross-conserved with other IAV, (iii) cross-conserved with human genome (HG) and other IAV, and (iv) human analogs of influenza epitopes. 91% of sequences bound to at least one of five common HLA II alleles and 61% displayed strong binding. Epitopes that are conserved with other IAV induced higher IFNγ responses; conversely, epitopes that were conserved with human genome (even though equally well conserved with IAV) induced 3 fold lower IFNγ responses, similar to the level induced by H7N9 unique epitopes and to human analogs of influenza epitopes. Stimulation of human PBMCs from healthy donors with HG cross-conserved epitopes increased the frequency of CD4+CD25+FoxP3+ T cell population. Low overall T cell epitope content and the presence of HG cross-conserved H7N9 T cell epitopes that activate Tregs may explain the very low sero-conversion rates to newly developed H7HA unadjuvanted vaccines. Exploration of alternative vaccine development approaches is warranted for this new influenza virus.