Senecavirus A (SV A) is an emerging picomavirus of swine that causes foot-and-mouth­(FMD)-like vesicular disease (VD) in affected animals. Currently, little is known about the mechanisms underlying SV A virulence and pathogenesis in pigs and there are no vaccines available for SV A in the US. The goals of the proposed study are to identify molecular determinants of SVA virulence and VD-pathogenesis in pigs and to use this information to rationally design effective and safe vaccine candidates for SVA. Recent work by our group, revealed a distinct pathogenicity profile between a historical and a contemporary SV A strains in pigs. We hypothesize that the genetic differences between these two phenotypical/y distinct strains may account for their distinct virulence phenotype and pathogenicity in pigs. Here, we propose to generate chimeric viruses based on a contemporary SVA backbone and containing specific genomic regions of the historical strain. The objectives of this study are: (1) To identify genetic determinants of SVA virulence and pathogenesis. (2) To evaluate the immunogenicity and protective efficacy of rationally attenuated SV A vaccine candidates.These objectives are related to the program area of Animal Health and Disease. The work will impact the priority areas of "Animal Products - Animal systems" and the sub priority area of "disease prevention" through "vaccines and vaccination delivery systems". The work proposed here will significantly contribute to the improvement and sustainability of the US livestock industry by generating basic knowledge and translating it into tools that can help to fight an important emerging disease of swine.