Novel MVA-based vaccine expressing influenza NP and M1 activates cross-reactive T cell responses in human nasopharynx-associated lymphoid tissue (NALT)

Abstract

Abstract Influenza virus infection continues to cause widespread morbidity and mortality, resulting in major challenges for healthcare systems. Current influenza vaccines are of limited efficacy against mismatched or emerging new virus strains. Recent efforts are focused on the development of novel vaccines capable of conferring broad protection against various influenza virus subtypes. We have studied the potential of Modified Vaccinia Ankara (MVA)-vectored vaccines expressing nucleoprotein and matrix protein 1 (MVA-NP+M1) to induce cross-reactive mucosal immunity using human adenotonsillar mononuclear cell (MNC) culture system with flow cytometry and ELISPOT analysis. Influenza NP and M1 antigens were abundantly expressed following vaccine stimulation in MNC particularly in B cells and dendritic cells. M1-specific T cell response was analyzed in detail, and MVA-NP+M1 was shown to activate IFN-γ-producing CD8+ T cells against conserved M1 epitopes. M158–66-specific CD8+ T cells in HLA-matched individuals were markedly increased in an age-dependent manner. These M1-specific T cells coexpressed cytotoxic molecules such as perforin and granzyme A and B. Upon the recognition of M158–66 peptide, these cells displayed marked increase in surface CD107a expression (implicating degranulation), together with the production of pro-inflammatory cytokines including IFN-γ and TNF-α, that correlated to their ability to kill the peptide-pulsed target cells. In summary, we showed MVA-NP+M1 activates conserved influenza antigen-specific cytotoxic T cell response in human NALT. The results suggest MVA-NP+M1 vaccine has the potential to induce cross-reactive mucosal T cell immunity against different types of influenza viruses.