** AWARDS ISSUED PRIOR TO JANUARY 20, 2025, WERE FUNDED UNDER PREVIOUS ADMINISTRATIONS AND MAY NOT REFLECT THE PRIORITIES AND POLICIES OF THE CURRENT ADMINISTRATION.** SWINE INFLUENZA CAUSED BY INFLUENZA A VIRUSES (IAVS) IS AN IMPORTANT RESPIRATORY DISEASE THAT CAUSES SIGNIFICANT ECONOMIC LOSSES FOR THE US SWINE INDUSTRY. ALTHOUGH SWINE INFLUENZA VACCINES HAVE BEEN WIDELY USED IN THE USA, SWINE INFLUENZA REMAINS INEFFECTIVELY CONTROLLED AND OUTBREAKS REMAIN A MAJOR AND GROWING PROBLEM FOR THE SWINE INDUSTRY. THE MAIN ISSUE IS THAT CURRENT SWINE VACCINES CANNOT KEEP UP WITH THE RAPID CHANGES OF CIRCULATING VIRUS STRAINS. THIS OFTEN LEADS TO VACCINES PROVIDING INEFFECTIVE CROSS-PROTECTION AGAINST DIFFERENT IAV STRAINS SUCH AS ANTIGENICALLY HETEROLOGOUS AND HETEROSUBTYPIC VIRUS STRAINS. COMMERCIALLY AVAILABLE SWINE LIVE ATTENUATED VACCINES (LAIVS) FROM BOEHRINGER INGELHEIM ANIMAL HEALTH OVERCOMES THE DISADVANTAGES OF TRADITIONAL KILLED VACCINES, BUT REASSORTS WITH CIRCULATING SWINE INFLUENZA VIRUSES. THIS HAS THE POTENTIAL TO GENERATE VIRULENT VIRUSES THAT COULD POSE A SIGNIFICANT THREAT TO ANIMAL AND HUMAN HEALTH. BECAUSE OF THE ISSUES WITH THE CURRENTLY AVAILABLE KILLED AND LIVE SWINE INFLUENZA VACCINE, THERE IS A CRITICAL NEED FOR SAFER AND EFFECTIVE SWINE INFLUENZA VACCINES.THE GOAL OF THIS PROJECT IS TO DEVELOP SAFE AND EFFECTIVE LIVE ATTENUATED SWINE INFLUENZA VACCINES USING NEWCASTLE DISEASE VIRUS (NDV) AS THE VECTOR. THIS APPROACH HAS POTENTIAL TO DEVELOP SAFER AND MORE EFFECTIVE SWINE INFLUENZA VACCINE. RECENTLY, WE SHOWED THAT NDV-BASED SWINE INFLUENZA VACCINE CAN PROVIDE COMPLETE PROTECTION IN PIGS AGAINST A HOMOLOGOUS SWINE INFLUENZA VIRUS CHALLENGE, INDICATING THE NDV-BASED VACCINE CAN BE USED IN PIGS. THEREFORE, WE HYPOTHESIZE THAT NDV-BASED SWINE INFLUENZA VACCINE CAN BE DEVELOPED AND HAS POTENTIAL TO PROVIDE CROSS-PROTECTION AGAINST DIFFERENT GENOTYPE AND SUBTYPE SIVS. ACCORDINGLY, OUR APPLICATION OFFERS A NOVEL STRATEGY TO PRODUCE SAFE AND EFFECTIVE SWINE INFLUENZA VACCINE USING THE NDV AS THE VECTOR. IF SUCCESSFUL, OUR STRATEGY HAS THE POTENTIAL TO REDUCE BOTH ANIMAL AND HUMAN INFLUENZA INFECTIONS, AND BLOCK POTENTIAL ZOONOTIC TRANSMISSION FROM SWINE TO HUMANS.DEVELOPMENT OF UNIVERSAL HUMAN AND SWINE INFLUENZA VACCINES IS IDEAL TO PROTECT PUBLIC AND ANIMAL HEALTH. HOWEVER, NO UNIVERSAL INFLUENZA VACCINE APPROACH HAS BEEN DEMONSTRATED TO BE FEASIBLE SO FAR. SUCCESSFUL COMPLETION OF THE TASKS IN THIS APPLICATION WILL OFFER AN ALTERNATIVE STRATEGY TO DEVELOP SAFE AND EFFECTIVE LIVE SWINE INFLUENZA VACCINE. FURTHERMORE, IT WILL PROVIDE IMPORTANT INSIGHT INTO HOW TO DEVELOP UNIVERSAL INFLUENZA VACCINES. SPECIFICALLY, PIGS HAVE BEEN DESCRIBED AS AN EXCELLENT MODEL FOR HUMAN INFLUENZA INFECTIONS BECAUSE SWINE HAVE CLINICAL MANIFESTATIONS AND PATHOGENESIS THAT IS HIGHLY SIMILAR TO THAT OF HUMAN INFECTIONS. THEREFORE, RESULTS OF THIS STUDY COULD PROVIDE INVALUABLE INSIGHTS INTO FUTURE VACCINATION STRATEGIES FOR HUMAN INFLUENZA VACCINES.