| The influenza virus infects millions of people each year and causes millions of dollars in economic loss. Traditional licensed vaccines usually provide limited protection and low efficacy against mismatched influenza strains, which leads to annual vaccinations and reformulations. The idea of one vaccine that protects all, called a "universal influenza vaccine," has been introduced. The novel in silico mosaic approach has been successfully used to construct broadly protective vaccines against variable HIV-1 viruses. Therefore, Modified Vaccinia Ankara, which expresses a mosaic H5 hemagglutinin (MVA-H5M), has been constructed to generate a broad H5 vaccine. This mosaic was generated in silico using 2,145 field-sourced H5N1 isolates. A single dose of MVA-H5M provided 100% protection against H5N1 virus clades 0, 1, 2.2 and 2.2.1, and it also protected against the H1N1 (PR8) virus. In addition, it provided short- (10 days) and long-term (6 months) protection post-vaccination. Immunological characterizations of MVA-H5M vaccines revealed that mosaic H5 elicited broader humoral and cellular immune responses over traditional native HA sequence vaccines. The homosubtypic protection elicited by MVA-H5M against the H5N1 virus correlates to antibodies, while heterosubtypic protection against the H1N1 virus correlates to CD8+ T cells. Studies also revealed that serum IgG could leak into the respiratory tract, which would help prevent viral infections in the respiratory tract. The mosaic H5 protein, expressed as a recombinant protein or DNA vaccine, still provided effective protection against the H5N1 virus, similar to MVA-H5M. Finally, the MVA-H5M vaccine provided heterosubtypic protection against pandemic H1N1 (A/Cal/04/09) and significantly reduced viral lung titers in non-human primates. Immunological studies also revealed that cross-reactive non-neutralizing antibodies triggered antibody-dependent cell cytotoxicity (ADCC) activities. The combination of T cells and ADCC elicited by MVA-H5M correlate to heterosubtypic protection in non-human primates. |
