Early vaccine mediated strain specific cytokine imbalance induces mild immunopathology during influenza infection.

Influenza A viruses (IAV) exist as distinct serological subtypes, with limited antibody cross reactivity compared to T cell responses, leading to universal vaccines that elicit robust T cell responses entering clinical trials to combat pandemic and zoonotic outbreaks. Previously we have extensively characterized the viral vectored universal vaccine, Wyeth/IL-15/5flu, a group 1 HA, H5N1 based vaccine using a vaccinia backbone with IL-15. The vaccine elicits robust T cell responses to provide heterosubtypic protection from lethal infection; however, we have also observed short-term morbidity of vaccinated mice with a disparity between the effects of sublethal infection with group 1 and 2 IAV strains. At day 3 of H3N2 (group 2 IAV) infection, there was a heavily skewed Th1 response in vaccinated infected mice with overproduction of cytokines and reduced chemokines, whilst H1N1 (group 1 IAV) infection had increased innate cellular responses. These findings suggest that increased and early immune activation by T cell activating vaccines may induce mild immunopathology when there is a mismatch between non-neutralizing antibody and cross-reactive memory T cell responses leading to exuberant cytokine production. Therefore, to avoid overstimulating proinflammatory immune responses upon infection, universal influenza vaccines that elicit strong T cell immunity will need a robust cross-reactive antibody response.