MVA-NP+M1 vaccine activates mucosal M1-specific T cell immunity and tissue-resident memory T cells in human nasopharynx-associated lymphoid tissue

Increasing evidences support a critical role of CD8+ T cell immunity against influenza. Activation of mucosal CD8+T cells, particularly tissue-resident memory T(TRM) cells recognizing conserved epitopes would mediate rapid and broad protection. Matrix protein 1(M1) is a well-conserved internal protein. We studied the capacity of Modified Vaccinia Ankara-vectored vaccine expressing nucleoprotein(NP) and M1(MVA-NP+M1) to activate M1-specific CD8+ T cell response including TRM cells in nasopharynx-associated lymphoid tissue(NALT) from children and adults. Following MVA-NP+M1 stimulation, M1 was abundantly expressed in adenotonsillar epithelial cells and B cells. MVA-NP+M1 activated marked IFN-γ-secreting T cell response to M1 peptides. Using tetramer staining, we showed the vaccine activated a marked increase in M158-66-specific CD8+ T cells in tonsillar mononuclear cells (MNC) of HLA-matched individuals. We also demonstrated MVA-NP+M1 activated a substantial increase in TRM cells exhibiting effector memory T cell phenotype. Upon recall antigen recognition, M1-specific T cells rapidly undergo cytotoxic degranulation, release granzyme B and pro-inflammatory cytokines, leading to target cell killing. Conclusion: MVA-NP+M1 elicits a substantial M1-specific T cell response including TRM cells in NALT, demonstrating its strong capacity to expand memory T cell pool exhibiting effector memory T cell phenotype, therefore offering great potential for rapid and broad protection against influenza reinfection.