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

Abstract

Influenza A viruses (IAVs) exist as distinct serological subtypes, with limited antibody cross reactivity compared with 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 hemagglutinin, H5N1‐based vaccine using a vaccinia backbone with interleukin (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 T helper type 1 response in vaccinated infected mice with overproduction of cytokines and reduced chemokines, whereas 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.

Help is on the way: critical roles of CD4+ T cells in infection and vaccination

“…The study conducted by Bull et al 4 . aimed to explore the effects of homosubtypic and heterosubtypic influenza A virus challenge following immunization with a universal flu vaccine that relies on CD4 + T cells to mediate protection in mice.…”

“…The study conducted by Bull et al 4 aimed to explore the effects of homosubtypic and heterosubtypic influenza A virus challenge following immunization with a universal flu vaccine that relies on CD4 + T cells to mediate protection in mice. Previous research had suggested that the correct balance of Th2 and Th1 cells is required to ensure Th2 cells can regulate the Th1 cell response to prevent immunopathology while enabling viral clearance.…”