Secondary heterosubtypic influenza infections result in radically different T cell immunodominance hierarchies and clinical outcomes (VIR5P.1137)

Abstract

Abstract When human populations face a novel subtype influenza A virus (IAV) with pandemic potential, the role of CD8+ cytotoxic T lymphocyte (CTL) responses targeting epitopes conserved or cross-reactive between the novel and previously encountered IAVs can be crucial to limit disease severity. To discover immune correlates of protective efficacy, we used a model of H7N9 secondary infections in mice primed by prior H1N1or H9N2 infection. Each priming case significantly, but variably, reduced disease morbidity and mortality, virus load, and time to virus clearance after H7N9 challenge. The sizes of the respective memory CTL pools were the best predictors of protective efficacy. The secondary CTL responses were characterized by earlier, significantly greater airway infiltration of H7N9 virus-specific CTLs but with distinct epitope immunodominance hierarchies among the dominant KbPB1703, DbPA224, and DbNP366 epitopes for each priming case. The epitope conservation between the priming and challenge viruses clearly influenced but alone did not consistently predict the immunodominance. The receptor repertoire of CTLs targeting a crossreactive and non-crossreactive DbNP366 epitope variant were characterized to reveal the nature of epitope cross-reactivity. These findings will contribute to understanding human CTL responses and rational design of CTL-mediated vaccines, where protective efficacy and immunodominance hierarchies may be highly sensitive to the immunological history of hosts.