Project Grant 20223353037150

BOVINE ALPHAHERPESVIRUS 1 (BOHV-1) IS ENDEMIC IN THE USA CATTLE POPULATION AND RESPONSIBLE FOR SIGNIFICANT ECONOMIC LOSS TO THE MILK AND BEEF INDUSTRIES. ALTHOUGH VACCINES ARE COMMERCIALLY AVAILABLE, NONE ARE COMPETENT TO PROTECT THE ANIMAL'S NERVOUS SYSTEM FROM BOHV-1 INVASION AND THE SUBSEQUENT ESTABLISHMENT OF LIFE-LONG LATENT INFECTIONS. IN ADDITION TO BEING THE SOURCE OF INFECTIOUS BOVINE RHINOTRACHEITIS (IBR), BOHV-1 IS A CAUSATIVE AGENT OF SHIPPING FEVER, WHICH RESULTS FROM STRESS PLACED ON CATTLE DURING SHIPPING THAT REACTIVATES LATENT INFECTION. IN FACT, CURRENT MODIFIED-LIVE VIRUS (MLV) VACCINES RETAIN NEUROINVASIVE AND LATENCY PROPERTIES AND CAN BECOME A COMPLICATING FACTOR CONTRIBUTING TO STRESS INDUCED REACTIVATIONS. THE FAILURE OF EXISTING PRODUCTS TO OFFER ADEQUATE PROTECTION TO CATTLE (FROM WEANING TO FEED YARDS) HAS HIGHLIGHTED THE NEED FOR A VACCINE THAT AFFORDS A COMBINATION OF STRONG HUMORAL AND CELL-MEDIATED IMMUNE RESPONSES, WHILE LACKING THE ABILITY TO ESTABLISH LIFE-LONG LATENT INFECTIONS IN THE NERVOUS SYSTEM. WE RECENTLY DEMONSTRATED THAT MLV VACCINES THAT REPLICATE IN NON-NEURAL TISSUE BUT ARE ABLATED FOR TRANSMISSION INTO THE NERVOUS SYSTEM, ELICIT PROTECTIVE IMMUNE RESPONSES WITHOUT EVOKING NEUROLOGIC COMPLICATIONS OR ESTABLISHING LIFE-LONG INFECTIONS. THIS VACCINE DESIGN, REFERRED TO AS R2, IS BASED ON THE REMOVAL OF A CRITICAL NEUROINVASIVE EFFECTOR REGION OF A VIRAL PROTEIN. THE SAFETY OF R2 VACCINES IS BASED ON THEIR INABILITY TO INVADE THE NERVOUS SYSTEM AND ESTABLISH LIFE-LONG LATENT INFECTIONS, AS OPPOSED TO BROADER REPLICATIVE ATTENUATION STRATEGIES THAT TRADITIONALLY TRY TO BALANCE VACCINE SAFETY WITH EFFICACY. UNLIKE TRADITIONAL BOHV-1 MLV DESIGNS, R2 VACCINES ARE CLEARED FROM THE BODY BY THE INDUCED IMMUNE RESPONSE. BY AVOIDING ATTENUATION OF BOHV-1 REPLICATION IN THE MUCOSA, R2 NON-INVASIVE VACCINES BREAK THE SAFETY-EFFICACY DILEMMA BY PRODUCING THE STRONGEST POSSIBLE IMMUNE RESPONSE WHILE MAINTAINING AN UNPRECEDENTED DEGREE OF SAFETY. IN THIS APPLICATION, WE WILL APPLY THE R2 DESIGN TO THE DEVELOPMENT OF A NEXT-GENERATION BOHV-1 VACCINE. THE R2 NON-NEUROINVASIVE VACCINE WILL BE TESTED FOR LOSS OF NEUROINVASIVE POTENTIAL AND VACCINE EFFICACY IN CALVES. THIS WORK WILL PROVIDE CRITICAL DATA FOR A PHASE II APPLICATION AND TO BRING THIS MUCH NEEDED PRODUCT TO MARKET.