PRRS modified live virus (MLV) vaccines have been licensed for clinical administration for over 20 years. The vaccines confer solid protection against homologous PRRSV strains. However, the extent and duration of protection against heterologous strains is highly variable and mostly sub-optimal. We recently generated a synthetic PRRSV strain (designated as PRRSV-CON) that is able to confer unprecedented levels of protection. In this project we characterized and compared the immune responses between pigs infected with a wild-type PRRSV strain and those infected with the PRRSV-CON. The primary goal is to determine the mechanisms by which the PRRSV-CON confers cross-protection, as this knowledge is useful for rational design of PRRS MLV vaccines in order to achieve optimal levels of heterologous protection. We found that the synthetic PRRSV-CON virus provides better levels of innate and adaptive immunity than the reference, wild-type PRRSV strain FL12. We are currently conducting further studies, with different experimental conditions, to determine how the difference in innate and adaptive immunity affects the protection outcomes.