Intranasal live vaccine harnesses pre-existing T cell memory for broad influenza protection

Respiratory tissue-resident memory T (TRM) cells recognize conserved epitopes and serve as key effectors against heterosubtypic IAV, but effective induction strategies remain elusive. Here we show that the CA4-dNS1 live attenuated influenza nasal spray vaccine confers broad heterosubtypic protection against circulating IAVs via pulmonary TRM induction, independent of cross-reactive antibodies.

Notably, pre-existing memory T cells, established by prior infection or intramuscular vaccination, are efficiently recruited by nasal boosting and differentiate into functional pulmonary TRM, substantially augmenting protective efficacy. Mechanistically, intramuscular priming expands the central memory T (TCM) pool, whereas nasal spray vaccination acts as a "portal-of-entry" immunization that both induces local TRM maturation and directs circulating TCM trafficking to the respiratory mucosa, thereby establishing a robust local immune barrier.