Adenoviral Vector-based Pandemic Influenza Vaccine

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PROJECT SUMMARY The ability of both low and highly pathogenic avian influenza (HPAI) viruses of H5, H7, and H9 subtypes to repeatedly infect humans reveals their zoonotic nature and pandemic potential. Besides, the seasonal influenza viruses (H1N1, H3N2 & influenza B) continue to evolve and pose significant public health threats worldwide. While candidate vaccine viruses can be made for individual influenza strains, it is impractical to prepare significant vaccine stocks for each of the potentially pandemic viruses. The significance of developing a universal influenza vaccine is of utmost importance for developing a better strategy for combatting seasonal as well as potential pandemic influenza viruses. We have developed a novel replication-defective bovine adenovirus (Ad) type 3 (BAd3)-based vaccine platform, which is better than the currently available Ad vector systems for providing heterologous influenza protection with dose sparing and is not impacted by the pre-existing human Ad vector immunity. Recently, we have revealed that the BAd vaccine platform induces significantly higher expression levels of the immunogen and innate and adaptive immunity-related factors compared to that of human Ad vectors in mice. We have also identified a 22 amino acid residues Autophagy-Inducing Peptide (AIP) C5 (AIP-C5) from the CFP10 protein of M. tuberculosis that enhances robust T cell immune responses in mice to NP of H7N9 influenza virus when delivered through an Ad vector. It conferred complete protection (from disease, death, or lung viral titers) against H1N1, H3N2, H5N2, H7N9, and H9N2 influenza viruses. Immunization of mice with an Ad vector expressing H5N1 M2e-HA2 [the extracellular domain of matrix 2 linked to the stem portion (HA2) of hemagglutinin (HA) with the HA signal peptide and the GCN4 leucine zipper trimerization domain] led to a significant reduction in lung viral titers following challenge with an H5N1 virus. This proposal is based on the hypothesis that a combination of heterosubtypic cell-mediated immune (CMI) responses against NP and the cross-reactive (not necessarily cross-neutralizing) humoral immune responses against NP or other conserved domains (M2e-HA2), when expressed with AIP-C5 and delivered through the BAd vaccine platform, will provide broad protection against potential pandemic H5, H7, or H9 avian influenza viruses as well as seasonal H1, H3, and influenza B viruses. The aims of this proposal are: i) To investigate immunogenicity and protective efficacy of novel antigen design and vaccine delivery platform in a mouse model for developing universal influenza vaccines (Aim 1); ii) To ascertain immunogenicity and protective efficacy of two selected universal influenza vaccine formulations in ferrets (Aim 2); and iii) To monitor virus transmission from the vaccinated to non-vaccinated animals, the quality of memory B and T cell responses, the durability of protective and vector immunity, and potential vaccine-associated enhancement of respiratory disease (Aim 3), utilizing the state-of-the-art technologies.