is a leading cause of bacterial gastroenteritis in humans around the world. The emergence of bacterial resistance is becoming more serious; therefore, development of new vaccines is considered to be an alternative strategy against drug-resistant pathogen. In this study, we investigated the pangenome of 173 strains and analyzed the phylogenesis and the virulence factor genes. In order to acquire a high-quality pangenome, genomic relatedness was firstly performed with average nucleotide identity (ANI) analyses, and an open pangenome of 8,041 gene families was obtained with the correct taxonomy genomes. Subsequently, the virulence property of the core genome was analyzed and 145 core virulence factor (VF) genes were obtained. Upon functional genomics and immunological analyses, five core VF proteins with high antigenicity were selected as potential core vaccine targets for humans. Furthermore, functional annotations indicated that these proteins are involved in important molecular functions and biological processes, such as adhesion, regulation, and secretion. In addition, transcriptome analysis in human cells and pig intestinal loop proved that these vaccine target genes are important in the virulence of in different hosts. Comprehensive pangenome and relevant animal experiments will facilitate discovering the potential core vaccine targets with improved efficiency in reverse vaccinology. Likewise, this study provided some insights into the genetic polymorphism and phylogeny of and discovered potential vaccine candidates for humans. Prospective development of new vaccines using the targets will be an alternative to the use of antibiotics and prevent the development of multidrug-resistant in humans and even other animals.