Extensive cell-mediated cross-reactivity between diverse influenza strains in the ferret model (VIR5P.1143)

Abstract

Abstract Influenza causes widespread epidemics affecting the world’s population. The virus achieves this on a yearly basis due to its ability to escape prior immunity by rapidly mutating surface proteins, the target of neutralizing antibodies. In contrast, the internal viral proteins, targets of the cell-mediated immune (CMI) response, are highly conserved, and have potential for cross-protection. However, little has been done to comprehensively evaluate the true extent of CMI cross-reactivity between influenza strains. Unvaccinated or vaccinated ferrets were challenged with 2008-2009 pandemic H1N1 influenza, A/Perth/16 (H3N2), or mock challenged. Cellular responses were examined 14d post-infection by stimulation with a diverse array of influenza viruses, and IFN-γ production by CD8+ and CD4+ T cells was assessed by flow cytometry. CMI responses exhibited extensive cross-reactivity across the majority of strains examined, but not to an unrelated virus, canine parainfluenza. Cross-reactivity was observed even between influenza A and B strains. While prior vaccination had little effect on the breadth of cross-reactivity, cross-reactive CD4+, but not CD8+ responses were heightened by prior vaccination. Challenge with pandemic H1N1 drove better cross-reactivity with B strains. These results confirm the widely held belief that CMI responses exhibit extensive cross-reactivity and extend this concept to strains considered antigenically distant such as influenza A and B strains.