** AWARDS ISSUED PRIOR TO JANUARY 20, 2025, WERE FUNDED UNDER PREVIOUS ADMINISTRATIONS AND MAY NOT REFLECT THE PRIORITIES AND POLICIES OF THE CURRENT ADMINISTRATION.** OUR TEAM'SPROPOSAL TACKLES A BIG PROBLEM AFFECTING CATTLE: THE IMPACT OF BOVINE RESPIRATORY SYNCYTIAL VIRUS (BRSV). BRSV IS A PRIMARY CAUSE OF RESPIRATORY DISEASE IN CATTLE AND IS ALSO A MAJOR PATHOGEN INVOLVED IN THE BOVINE RESPIRATORY DISEASE COMPLEX (BRDC) IN CALVES, THE MOST COSTLY CAUSE OF INFECTION-RELATED ECONOMIC LOSSES ACROSS THE BEEF AND DAIRY SECTORS. CURRENT VACCINES OFFER VARIABLE EFFICACY AND HAVE RAISED SAFETY CONCERNS, UNDERSCORING THE NEED FOR INNOVATIVE SOLUTIONS. OUR MAIN GOAL IS TO PIONEER THE DEVELOPMENT OF A NOVEL SINGLE CYCLE VACCINE STRATEGY THAT PROMISES NOT ONLY EFFICACY BUT ALSO HEIGHTENED SAFETY.SINGLE-CYCLE VACCINES CONSIST OF A LIVE-ATTENUATED VERSION OF A PATHOGEN. ALTHOUGH CATEGORIZED AS LIVE VACCINES, SINGLE-CYCLE VACCINES ARE UNABLE TO FULLY REPLICATE IN ANIMALS. THIS TYPE OF VACCINE OPERATES INGENIOUSLY: THE VIRUS HAS THE ABILITY TO INFECT ANIMAL CELLS AND, LIKE ANY OTHER VIRUS, USES THE HOST CELL TO GENERATE VIRAL PROTEINS. THE INFECTION OF THE HOST AND THE PRODUCTION OF THESE MANY VIRAL PROTEINS TRIGGERSAN IMMUNE RESPONSE AGAINST THE VIRUS.HOWEVER, OUR VACCINE IS DESIGNED TO PREVENT THE VIRUS FROM EVER COMPLETING ITS REPLICATION CYCLE. ALTHOUGH THE VIRUS PRODUCES MOST OF THE PROTEINS NECESSARY FOR REPLICATION, ONE ESSENTIAL PIECE IS MISSING, PREVENTING THE FORMATION OF INFECTIOUS VIRUS PARTICLES. THIS MEANS THAT THE ANIMAL'S IMMUNE SYSTEM CAN LEARN TO COMBAT THE VIRUS USING A REAL VIRUS MODEL, BUT WITHOUT THE RISK OF THE VIRUS IN THE VACCINE SPREADING. ADDITIONALLY,WEARE FOCUSING ON MAKING A VACCINE THAT CAN BE GIVEN THROUGH THE NOSE, WHICH IS NOT ONLY EASIER TO ADMINISTER BUT ALSO LEADS TO ANTIBODIES AND IMMUNE CELLS BEING LOCATED AT MUCOSA SITES, WHERE INFECTIONS USUALLY TAKE PLACE. NASAL VACCINES ALSO AVOID ISSUES WITH THE CALF'S IMMUNE SYSTEM ELIMINATING THE VACCINE BEFORE IT CAN TRIGGER THE ANIMAL'S IMMUNE SYSTEM. THIS ISSUE ARISES IN YOUNG ANIMALS FROM INTERFERENCE BY MATERNAL ANTIBODIES, WHICH ARE PASSED ON THROUGH COLOSTRUM INGESTION (MATERNAL IMMUNITY).SINGLE-CYCLE VACCINES FUNCTION THROUGH THE RATIONAL DESIGN OF DELETIONS OR MODIFICATIONS IN THE BRSV GENES NECESSARY FOR VIRAL PARTICLE FORMATION AND INFECTIVITY. THIS STRATEGY ENSURES THE VACCINE'S SAFETY BY ELIMINATING THE POSSIBILITY OF VIRUS SHEDDING AND REVERSION TO A VIRULENT FORM.OUR PROPOSAL OUTLINES THREE PRINCIPAL OBJECTIVES: (1) THE CREATION OF A SINGLE-CYCLE BRSV VACCINE IN WHICH THE ESSENTIAL VIRAL MATRIX PROTEIN GENE IS ABSENT, PREVENTING THE GENERATION OF PROGENY SINCE THE M PROTEIN IS A NECESSARY COMPONENT OF THE VIRAL PARTICLE (TERMED MNULL BRSV SINGLE-CYCLE VACCINE); (2) THE DEVELOPMENT OF A SECOND SINGLE-CYCLE VACCINE IN WHICH ALL ESSENTIAL VIRAL PROTEINS ARE PRESENT, BUT IN WHICH THE VIRAL FUSION PROTEIN IS MODIFIED TO LOSE ITS FUNCTION (PREF BRSV SINGLE-CYCLE VACCINE). THIS CHANGE RENDERS THE VIRUS UNABLE TO SPREAD AFTER A FIRST CYCLE IN THE HOST, AS THE FUSION PROTEIN IS NECESSARY FOR THE VIRUS TO BIND TO AND EN,TER HOST CELLS. IT IS ONLY POSSIBLE TO GROW THESE VIRUSES UNDER LABORATORY SETTINGS WITH THE HELP OF UNIQUE CELL LINES ESPECIALLY DEVELOPED TO PROVIDE THE MISSING VIRAL PROTEIN (IN THE CASE OF THE MATRIX PROTEIN) OR TO COMPLEMENT THE FUNCTION OF THE MODIFIED PROTEIN (IN THE CASE OF THE FUSION PROTEIN). WE WILL THEN (3) CARRY OUT THE EVALUATION OF THESE VACCINES' IMMUNOGENICITY AND EFFICACY IN CALVES. THIS INITIATIVE BUILDS UPON OUR PRIOR RESEARCH AND APPLIES PROVEN SINGLE-CYCLE REPLICATION TECHNOLOGIES TO BRSV, AIMING TO PRODUCE VACCINE PROTOTYPES THAT ARE BOTH BROADLY EFFECTIVE AND EXCEPTIONALLY SAFE.THE ANTICIPATED OUTCOME OF OUR PROJECT IS THE GENERATION OF A MUCOSAL SINGLE-CYCLE BRSV VACCINE PROTOTYPE THAT IS BOTH HIGHLY EFFECTIVE AND VERY SAFE, PROMISING A SIGNIFICANT ADVANCEMENT IN THE FIGHT AGAINST BRDC IN CALVES. THIS COULD HAVE A BIG IMPACT ON THE CATTLE INDUSTRY BY KEEPING CALVES HEALTHIER, REDUCING THE NEED FOR ANTIBIOTICS, AND SAVING FARMERS MONEY. ULTIMATELY, OUR PROJECT AIMS TO SOLVE A MAJOR PROBLEM IN ANIMAL HEALTH, BENEFITING BOTH ANIMALS AND THE PEOPLE WHO RELY ON THEM.