Hemagglutinin (HA)-specific antibodies directly bind the virus and prevent its entry into host cells, providing narrow immunity from reinfection by closely related strains. CD8 T cell responses to IAV generated against highly conserved viral proteins/epitopes contribute to clearance of virus during primary IAV infection and also confer broad heterosubtypic protection in animal models. Recent evidence links the cross-reactive CD8 T cell response in man to reduced viral replication and protection from severe illness in pandemic H1N1 infections in European populations, and H7N9 infections in China. Because pre-existing T-cell immunity, independent of baseline antibodies, protects against symptoms and viral shedding associated with influenza, influenza vaccines that stimulate broadly reactive CD8 T cell responses may have the capacity to protect against any pandemic influenza A virus. Human infections with H5N1 and H7N9 avian IAV and the 2009 H1N1 pandemic have spurred an interest in the development of vaccines against IAV with pandemic potential. Major challenges to this effort include our inability to predict which virus will emerge and rapid production and deployment of vaccine if the virus spreads rapidly and vaccine yield is not optimal. In addition, the number of doses of vaccine required depends on whether the population is immunologically naive. Therefore, vaccine technologies that elicit broadly cross-reactive and protective immune responses against a range of influenza viruses and that can be scaled-up are desirable. We compared the efficacy of two intranasally delivered non-replicating vaccines (H1 and H5 S-FLU) that are based on the suppression of the hemagglutinin signal sequence, with the corresponding H1N1 and H5N1 cold-adapted (ca) live attenuated influenza vaccines in mice and ferrets. Administration of two doses of H1 or H5 S-FLU vaccines protected mice and ferrets from lethal challenge with homologous, heterologous and heterosubtypic influenza viruses and two doses of S-FLU and ca vaccines were comparable. Importantly, when ferrets vaccinated with one dose of H1 S-FLU or ca vaccine were challenged with the homologous H1N1 virus, the challenge virus failed to transmit to naive ferrets by the airborne route. S-FLU technology can be rapidly applied to any emerging influenza virus and the promising preclinical data support further evaluation in humans.
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