Influenza A viruses (IAVs) belonging to H1 and H3 subtype are a major cause of respiratory disease outbreaks in swine worldwide. Influenza A viruses of swine (IAV-S) are zoonotic and antigenically related to human IAVs, posing pandemic threat to humans in addition to the significant economic burden to the pork industry. Antigenic drift and antigenic shift lead to a substantial antigenic diversity of circulating IAV-S strains. As a result, the most used vaccines based on whole inactivated viruses (WIV) provide low protection against divergent IAV-S strains due to the mismatch between the vaccine virus strain and the circulating strains. Here, I hypothesize that broadly protective immunity against divergent IAV-S can be achieved by delivering consensus and chimeric HA glycoproteins. These broadly protective antigens will be delivered using a poxviral vector platform that is well characterized and known to be safe and highly immunogenic in swine. This hypothesis will be tested by a) characterizing the breath of humoral and cellular responses elicited by the consensus and chimeric HA platforms, and b) determining the protective efficacy and breath of protection elicited by these platforms in swine. The design of consensus HA sequences based on contemporary virus isolates minimizes the genetic and antigenic distances between candidate vaccine platforms and circulating viruses, thus potentially enhancing protection against heterologous circulating wild-type viruses. Whereas the HA-stalk-based approach relies on the fact that re-directing the immune responses towards the conserved and subdominant stalk domain of HA by breaking the immunodominance of the HA head domain through sequential immunization with vaccine platforms comprising chimeric HAs will induce cross-protection. Briefly, a consensus coding sequence of the full-length of HA from H1 subtype was generated in silico after alignment of the sequences from recent IAV-S isolates obtained from public databases, subcloned into a poxviral transfer vector and finally inserted into the ORFV121 locus of Orf virus by homologous recombination. Whereas the chimeras’ coding sequences for H1 subtype were designed based on the stalk domain of a recent H1N1 Swine Influenza A virus (IAV-S) strain, and the heads were chosen based on subtypes that are not found to cause disease in swine species. Here, I propose to evaluate the immunogenicity and protective efficacy of these multivalent vaccine platforms in swine against divergent clades of H1 subtype of IAV-S. Antibody responses will be evaluated against whole virus IgG-ELISA optimized for a panel of divergent H1 viruses circulating in swine and by virus neutralization. Also, antibody-dependent cell-mediated cytotoxicity (ADCC) assays will be performed since it is likely that most antibodies against conserved epitopes - such as the ones present on the stalk domain of HA - are non-neutralizing and inhibit the virus by enhancing T-cell cytotoxicity activity through recognition of the antibody Fc domain. Additionally, IAV-S-specific T cell responses will be assessed by T cell proliferation assays using intracellular cytokine staining (ICS) assay to measure IFN-ƴ production by different T cell subtypes and flow cytometry to determine the populations of T cells and their level of response to the vaccine platforms prior and after infection compared to sham-immunized/infected animals. Protection against the disease will be determined by assessing viral replication and shedding through respiratory secretions, viral load in lungs, lung pathology and clinical score.