Protection by universal influenza vaccine is mediated by memory CD4 T cells

There is a diverse array of influenza viruses which circulate between different species, reassort and drift over time. Current seasonal influenza vaccines are ineffective in controlling these viruses. We have developed a novel universal vaccine which elicits robust T cell responses and protection against diverse influenza viruses in mouse and human models. Vaccine mediated protection was dependent on influenza-specific CD4⁺ T cells, whereby depletion of CD4⁺ T cells at either vaccination or challenge time points significantly reduced survival in mice. Vaccine memory CD4⁺ T cells were needed for early antibody production and CD8⁺ T cell recall responses. Furthermore, influenza-specific CD4⁺ T cells from vaccination manifested primarily Tfh and Th1 profiles with anti-viral cytokine production. The vaccine boosted H5-specific T cells from human PBMCs, specifically CD4⁺ and CD8⁺ T effector memory type, ensuring the vaccine was truly universal for its future application. These findings have implications for the development and optimization of T cell activating vaccines for universal immunity against influenza.