Universal influenza vaccinia vaccine requires CD4+ T cells for heterosubtypic protection

Abstract

Background Current influenza vaccines are ineffective against novel viruses and the source or strain of the next outbreak of influenza is unpredictable, therefore establishing universal immunity by vaccination is fundamental to limiting the impact of influenza. It is essential to improve influenza vaccines by utilizing multiple arms of the immune system. Virus specific CD4+ and CD8+ T cells responses are able to directly kill virus infected cells and co-ordinate local innate immune responses. Importanlty, T cells are able to react against different strains and subtypes of influenza. A novel vaccine has been developed using the immunogenic live vaccinia virus as a vaccine vector, containing multivalent influenza proteins derived from H5N1, plus IL-15 as an adjuvant. Previously, this vaccine demonstrated robust sterile cross-clade protection in mice for H5 influenza viruses, and here its use has been extended to mediate heterosubtypic immunity towards more distant group 1 and group 2 influenza viruses. Materials and methods Heterologous protection by the vaccine was assessed in the BalbC and B6 mouse models. T cell responses elicited after vaccination and following influenza virus challenge were measured by Intracellular cytokine staining (ICS) assay. The T cell compartment was selectively depleted by monoclonal antibody treatments. Results The vaccine is able to induce robust immunological T cell memory, enabling the survival of mice against challenge with many different influenza viruses. The vaccine protected mice against lethal challenge by increasing survival and significantly reducing virus loads against the most recent human H7N9, seasonal H3N2, pandemic-2009 H1N1 and highly pathogenic H7N7 influenza A viruses. Influenza-specific antibody responses were Sopable to mediate protection by passive transfer. Importantly, influenza specific CD4+ and CD8+ T cell responses are elicited by the vaccine, and recruited following viral challenge in the lung and periphery. Selective depletion experiments for T cell subsets revealed an important role of CD4+ T cells in heterosubtypic protection depsite low peptide MHC-II epitope sequence conservation across different influenza viruses. Memory T cell responses were found to act in synergy with higher viral loads in mice depleted of both CD4+ and CD8+ T cell responses. Conclusions This study has illustrated the potential use of multivalent-vaccinia virus as a universal influenza vaccine. The vaccine established influenza specific CD4+ and CD8+ T cell responses, which were significantly larger upon viral challenge. We have established an essential role of CD4+ T cells in providing universal protection against influenza established by a vaccinia-H5N1 vaccine.