INCREASING THE BREADTH OF PROTECTION AFFORDED BY INFLUENZA A VIRUS VACCINES FOR SWINE BY TARGETING THE MATRIX PROTEIN 2

This proposal addresses disease prevention by vaccinating pigs against swine influenza A virus (swIAV). The economic losses resulting from swine influenza rank among the top three health challenges to the pork industry. Protection of swine by commercial IAV whole inactivated virus (WIV) vaccines is limited in part due to co-circulation of multiple strains of antigenically distinct viruses in the same region that differ in the subtype of hemagglutinin (HA) they express. Notably, >98% of IAV strains circulating in U.S. swine herds share the same matrix protein 2 (M2) isoform, which is displayed on the virus envelope. We have determined that immunization of swine with a novel M2 vaccine formulation, consisting of recombinant full-length M2 displayed in its natural trans-membrane configuration, elicits M2-specific IgG capable of recognizing IAV virions, as well as M2-specific interferon-gamma secreting T cells. Given that the M2 virus envelope protein contributes to protective immunity in swine, the goal of this project is to test the hypothesis that the immunization of swine with WIV vaccines supplemented with M2 broadens their breath of protection conferred to include antigenically distinct swIAV strains within the same hemagglutinin (HA) subtype.To accomplish our goal, we propose three objectives: 1. Assessment of the ability of M2 to increase the breadth of coverage afforded by influenza WIV vaccines against antigenically distinct IAV. 2. Optimization of M2 construction and assessment of the oligomerization state of M2. 3. Assessment of the immunogenicity of M2 that incorporate immune-stimulatory molecules. The first objective is designed to test the hypothesis listed above using our novel M2 antigen assemblies. We have already shown that our M2 assemblies are able to elicit strong M2-specific humoral and cellular immunity and, thus, would be expected to provide some level of protective immunity. The second objective is aimed at improving on our already functioning M2 assemblies by confirming that M2 is optimally displayed to be as immunogenic as possible. The third objective is aimed at possibly improving the immunogenicity of the M2 assemblies by directly inserting into them immune-stimulating molecules that would serve as adjuvants.