This project is based on two main premises: 1) the conviction that the use of vaccines will always be a cost-efficient method and the preferred approach to control PRRSV infections, and 2) the notion that the best type of vaccine against PRRSV has proved to be the live, attenuated vaccines. In all likelihood, the live vaccines are most effective because their components that are determinants of protection ( a.k.a as antigens or immunogenic epitopes) are “seen” by the pig in a similar way as the animal “sees” those of live wild-type (fully infectious) PRRSV. Our ultimate goal is to develop a live vaccine of safety and efficacy that would be compatible with the ability of cleansing the PRRSV infection, that is, compatible with the ability of differentiating, through a simple test, the vaccinated/protected animals from those that have suffered infection by wild-type PRRSV. Our technical approach to the improvement of PRRS live vaccines is based on the notion that mapping the genes causing virulence in PRRSV should provide information for the development of a differential PRRSV vaccine of unprecedented safety and efficacy. The capacity of PRRSV to cause serious pathologic changes is called virulence. In our system we measure viral virulence in relation to the virus’ ability of producing abortion in pregnant sows. This virulence is caused by the different genes and its proteins composing the PRRSV. The main expected outcome of this research is the alteration of the genes of the PRRS viruses to develop live attenuated/marker vaccine strains. Engineering of new live-attenuated PRRSV marker vaccines requires knowledge of the genetic make-up of PRRS virulence and identifying small areas of the proteins which can be eliminated from the vaccine without affecting the virus’ ability to multiply in the pig. This concept is the same principle applied in the case of Pseudorabies marker vaccines. The differential vaccines, which, like in the example of Pseudorabies, were originally called “marker vaccines” are now also identified as DIVA vaccines (which stands for “Differentiating Infected from Vaccinated Animals”). This year we report the identification of two major genes (ORF5 and ORF2) that are base of PRRSV virulence. Likewise we have discovered a large series of small segments of PRRSV proteins (epitopes) that could be deleted from the live vaccine so that could then be used as serologic diagnostic markers of infection (DIVA markers).