A vaccine platform targeting lung-resident memory CD4(+) T-cells provides protection against heterosubtypic influenza infections in mice and ferrets.

Lung tissue-resident memory T (T(RM)) cells induced by influenza vaccination are crucial for heterosubtypic immunity upon re-exposure to the influenza virus, enabling rapid and robust responses upon reactivation. To enhance the efficacy of influenza vaccines, we induce the generation of lung T(RM) cells following intranasal vaccination with a commercial influenza vaccine adjuvanted with NexaVant (NVT), a TLR3 agonist-based adjuvant. We demonstrate that intranasal immunization with the NVT-adjuvanted vaccine provides improved protection against influenza virus infections by inducing the generation of CD4(+) T(RM) cells in the lungs in a type I interferon-dependent manner. These pulmonary CD4(+) T(RM) cells provide potent mucosal immunity and cross-protection against heterosubtypic infections in both mouse and ferret models. This vaccine platform has the potential to significantly improve conventional intramuscular influenza vaccines by providing broader protection.