**AWARDS ISSUED PRIOR TO JANUARY 20, 2025, WERE FUNDED UNDER PREVIOUS ADMINISTRATIONS AND MAY NOT REFLECT THE PRIORITIES AND POLICIES OF THE CURRENT ADMINISTRATION.** PORCINE REPRODUCTIVE RESPIRATORY SYNDROME VIRUS (PRRSV), WHICH IS A SIGNIFICANT THREAT TO THE SWINE INDUSTRY, MUTATES CONSTANTLY AND AS A RESULT MANY DIFFERENT STRAINS CIRCULATE IN THE FIELD. THIS IS THE MAJOR CHALLENGE FACED IN THE CONTROL OF PRRS. WITH TWO MAJOR GENOTYPES, A NUMBER OF SUB-GENOTYPES AND MANY DIFFERENT CIRCULATING STRAINS WITHIN EACH ONE, A NEXT GENERATION OF VACCINES TAILORED TO EFFECTIVELY CROSS-PROTECT SWINE ARE IN HIGH DEMAND. A NOVEL DISCOVERY TOOL THAT ALLOWS ASSEMBLY OF SETS OF MOSAIC PROTEINS FROM FRAGMENTS OF NATURAL SEQUENCES AS POLYVALENT VACCINES RECENTLY CREATED AT THE LOS ALAMOS NATIONAL LABORATORY TO COMBAT HIV, ANOTHER HIGHLY VARIABLE RNA VIRUS, INCREASES SIGNIFICANTLY VACCINE CROSS-PROTECTION IN NON-HUMAN PRIMATES, AND IN HUMANS. THE MOSAIC VACCINE TECHNOLOGY POTENTIAL TO CROSS-PROTECT SWINE AGAINST DIVERGENT PRRSV STRAINS WAS RECENTLY TESTED IN OUR LABORATORY WITH PROMISING RESULTS. IN BRIEF, A CROSS-PROTECTIVE CAPACITY AGAINST CHALLENGE WITH TWO DIVERGENT STRAINS (VR2332 AND MN184) WAS DEMONSTRATED USING A VIRUS PROTEIN (GP5) AS MOSAIC VACCINE THAT REPRESENTS OVER 748 NATURAL SEQUENCES OF CIRCULATING VIRUSES. THE PRESENT INVESTIGATION AIMS AT STRENGTHENING THESE ENCOURAGING RESULTS ACHIEVED WITH OUR GP5 MOSAIC VACCINE. WE WILL TEST THE HYPOTHESIS THAT MULTIVALENT MOSAIC VACCINES THAT INCLUDE OTHER STRUCTURAL VIRAL PROTEINS IN A MOSAIC FASHION WILL INCREASE SIGNIFICANTLY THE CROSS-PROTECTION AGAINST DIVERSE PRRS VIRUS STRAINS ACHIEVED THUS FAR WITH A VACCINE CARRYING ONLY A SINGLE GP5 MOSAIC PROTEIN.