Vaccine-generated lung tissue-resident memory provides heterosubtypic protection to influenza infection

Abstract Tissue-resident memory T cells (TRM) comprise a non-circulating subset which provides robust in situ protection upon infection. It is increasingly recognized that vaccination strategies promoting TRM may convey enhanced protection from disease. However, it is unclear whether currently available vaccines elicit TRM and whether this is dependent on vaccine formulation or administration route. In the context of influenza, we assessed lung TRM generation and subsequent protection following vaccination with either injectable inactivated influenza virus (IIV, Fluzone®) or intranasal live-attenuated influenza virus (LAIV, FluMist®) vaccines. We found that IIV induced primarily neutralizing antibodies while LAIV generated robust lung T cell responses. Importantly, LAIV, but not IIV, established persisting lung CD4 and CD8 TRM similar in localization and phenotype to that generated by influenza infection. Furthermore, protection experiments utilizing the immunomodulatory drug FTY720, which sequesters circulating T cells, including TEM and TCM, in secondary lymphoid tissues leaving lung TRM intact, demonstrated that only LAIV provided TRM-mediated protection to viral infection as evidenced by reduced weight loss and lung viral titers in this group following infection. Importantly, TRM generation and protection were dependent on both route and vaccine formulation. The ability of LAIV to generate lung TRM protective against non-vaccine viral strains may have important implications in providing protection in pandemic situations.