**AWARDS ISSUED PRIOR TO JANUARY 20, 2025, WERE FUNDED UNDER PREVIOUS ADMINISTRATIONS AND MAY NOT REFLECT THE PRIORITIES AND POLICIES OF THE CURRENT ADMINISTRATION.** PROBLEM: SWINE INFLUENZA VIRUS INFECTIONS HAVE A SIGNIFICANT IMPACT ON THE PORK INDUSTRY, WITH ONE STUDY ESTIMATING OVER $700,000,000 IN LOSSES IN THE USA. IN ADDITION, PIGS ARE SUSCEPTIBLE TO HUMAN, AVIAN, AND SWINE INFLUENZA AND ARE EXCELLENT MIXING VESSELS FOR REASSORTED INFLUENZA STRAINS LEADING TO INCREASING GENETIC DIVERSITY. THEREFORE, ZOONOSIS EVENTS CAN LEAD TO HUMAN INFECTION WITH VARIANT SWINE INFLUENZA WHICH HAPPENS MORE FREQUENTLY THAN MOST PEOPLE REALIZE. SINCE 2005 THERE HAVE BEEN MORE THAN 400 SWINE VARIANT INFLUENZA INFECTIONS IN THE UNITED STATES. THE 2009 H1N1 SWINE FLU PANDEMIC THAT INFECTED ¼ OF THE GLOBAL POPULATION IS A PERFECT EXAMPLE OF THIS ZOONOSIS. IN MARCH OF 2009, AN H1N1 SWINE INFLUENZA EMERGED IN MEXICO AND THE UNITED STATES IN BOTH CALIFORNIA AND TEXAS. THIS NOVEL SWINE FLU CIRCULATED THE GLOBE, CAUSED WORLDWIDE PANIC, FORCED THE CLOSING OF STATE FAIRS AND INFECTED 24% OF THE WORLD'S POPULATION. UNFORTUNATELY, THE CURRENT COMMERCIAL SWINE INFLUENZA VACCINES HAVE LIMITED STRAIN COVERAGE AND ARE INFREQUENTLY UPDATED. MISMATCHED VACCINES PROVIDE LITTLE OR NO PROTECTION AND, IN THE CASE OF SWINE INFLUENZA, CAN LEAD TO VACCINE-ASSOCIATED ENHANCED RESPIRATORY DISEASE (VAERD).SOLUTION: A UNIVERSAL SWINE INFLUENZA VACCINE THAT WOULD REDUCE THE ECONOMIC IMPACT OF SWINE INFLUENZA ON THE PORK INDUSTRY, ALONG WITH REDUCING THE PROBABILITY OF EMERGENT ZOONOTIC REASSORTED INFLUENZA VIRUSES INTO THE HUMAN POPULATION. WE PROPOSE THE USE OF OPTIMIZED VACCINE PROTEINS THAT HAVE BEEN DESIGNED TO INDUCE BROADER CROSS-REACTIVE IMMUNITY AGAINST DIVERGENT VIRUS STRAINS AS COMPARED TO WILDTYPE PROTEINS. THESE OPTIMIZED VACCINE STRATEGIES MAY BE INSTRUMENTAL IN THE PRODUCTION OF A UNIVERSAL VACCINE. IN THIS PROPOSAL, WE DESCRIBE THE PRODUCTION OF FOUNDATIONAL EPIGRAPH INFLUENZA PROTEINS FOR USE AS UNIVERSAL SWINE INFLUENZA VACCINES. OUR VACCINE TARGET IS THE HEMAGGLUTININ PROTEIN (HA), WHICH IS THE PRIMARY TARGET FOR NEUTRALIZING ANTIBODIES OF INFLUENZA. WE WILL TEST THESE EPIGRAPH VACCINE PROTEINS FOR THEIR ABILITY TO INDUCE PROTECTION AGAINST DIVERGENT H3N2 SWINE INFLUENZA A VIRUSES AND EVALUATE THEIR POTENTIAL AS A UNIVERSAL VACCINE. H3N2 WAS SELECTED DUE TO SIGNIFICANT AGRICULTURAL BURDEN, HIGH GENETIC DIVERSITY, AND INCREASING NUMBER OF ZOONOTIC EVENTS RECENTLY DOCUMENTED. RESULTS FROM THIS PROPOSAL COULD FURTHER BE APPLIED TO H1 SWINE INFLUENZA VIRUSES IN FUTURE STUDIES. OUR PRELIMINARY DATA FROM MICE AND SWINE INDICATES THAT EPIGRAPH VACCINES INDUCE SUPERIOR PROTECTION AGAINST MISMATCHED CHALLENGE VIRUSES AS COMPARED TO WILDTYPE HA VACCINES AND COMMERCIAL VACCINES.

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