THE VAST GENETIC AND ANTIGENIC VARIABILITY OF VIRUSES LIKE THE PORCINE REPRODUCTIVE AND RESPIRATORY DISEASE SYNDROME VIRUS (PRRSV) AND INFLUENZA POSE A LONG-STANDING CHALLENGE IN THE FIELD OF VACCINOLOGY. THE PHENOMENON OF ANTIBODY BASED IMMUNODOMINANCE, WHEREIN THE INFECTING VIRUS DIRECTS THE IMMUNE SYSTEM TO PRODUCE WASTEFUL RATHER THAN PROTECTIVE ANTIBODY RESPONSES TO ESCAPE HOST IMMUNITY, ALSO SERVES AS A MAJOR CONFOUNDING FACTOR FOR EFFECTIVE VACCINE DEVELOPMENT. FURTHER, THE EARLY UNDERMINING OF THE IMMUNE RESPONSE RESULTS IN THE AMPLIFICATION OF THE SUBOPTIMAL RESPONSE WITH EVERY SUBSEQUENT INFECTION OR BOOSTER VACCINATION, THUS INCREASINGLY DIMINISHING VACCINE EFFICACY AGAINST NEWLY EMERGING VARIANTS WITH AGE.THEREFORE, A MAJOR GOAL OF THIS PROJECT IS TO RATIONALLY RE-ENGINEER THE IMMUNODOMINANCE PATTERNS OF SELECTED PRRSV VACCINE ANTIGENS TO IMPROVE THE QUALITY OF THE ANTIBODY RESPONSE OF PRRSV VACCINES. A SECONDARY GOAL OF THE PROJECT IS TO DEVELOP THE PRRSV VACCINE AS A DELIVERY SYSTEM FOR OTHER SWINE VIRAL VACCINE ANTIGENS, TO REDUCE THE COST AND EFFORT ASSOCIATED WITH VACCINATION. PORCINE CIRCOVIRUS TYPE 3 IS A NEWLY EMERGED SWINE VIRUS WHICH ALSO CAUSES REPRODUCTIVE AND RESPIRATORY DISEASE IN PIGS. IT IS VERY FREQUENTLY CO-DETECTED WITH PRRSV. HENCE, THE RATIONALLY DESIGNED PRRSV VACCINE WILL BE ENGINEERED TO ALSO DELIVER THE PCV3 VACCINE ANTIGEN SIMULTANEOUSLY TO VACCINATED PIGS. TO TEST THE DUAL PRRSV-PCV3 VACCINE, GROUPS OF PIGS WILL BE VACCINATED WITH THE CONSTRUCT, WHILE CONTROL PIGS WILL EITHER REMAIN UNVACCINATED OR RECEIVE A COMMERCIAL VACCINE. AFTER ALLOWING TIME FOR THE DEVELOPMENT OF THE IMMUNE RESPONSE, THE VACCINATED PIGS WILL BE EXPOSED TO PRRSV AND PCV3 VIRUSES. IT IS EXPECTED THAT VACCINATION WILL RESULT IN PROTECTION AGAINST PRRSV DISEASE MANIFESTATIONS AND ELICIT IMPROVED ANTI-PRRSV ANTIBODY RESPONSES, AND THAT VACCINATED PIGS WILL ALSO BE PROTECTED AGAINST PCV3 REPLICATION AND PATHOLOGY. WE EXPECT THAT THE PROJECT OUTCOMES WILL SIGNIFICANTLY IMPROVE PRRSV VACCINE PERFORMANCE, PROVIDE A TEMPLATE FOR IMPROVING CURRENT VACCINES AGAINST GENETICALLY VARIABLE VIRUSES AND DEVELOP THE PRRSV VACCINE AS A DELIVERY SYSTEM FOR MULTIPLE SWINE INFECTIONS.