is a significant pathogen in pigs and a newly emerging zoonotic agent in humans. The presence of multiple serotypes and strains with diversified sequence types in pig herds highlights the need for the identification of broadly cross-reactive universal vaccine antigen targets, capable of providing cross-protection against infection. Subunit vaccines based on the conserved proteins shared between different serotypes are potential candidates for such a universally protective vaccine. In the present study, phosphate ABC transporter ATP-binding protein PstB (PstB), an immunogenic protein of the bacterium, was expressed and purified, and then subjected to cross-protection evaluation in mice. The PstB protein showed nearly 100% amino acid similarity across a panel of 31 isolates representing different serotypes, which were collected from different countries. A recombinant PstB (rPstB) protein ( serotype 2) was recognized by rabbit sera specific to this serotype, and induced high levels of IFN-γ and IL-4 in mice immunized with the recombinant protein. These cytokines are considered important for protection against infection. Immunization of mice with rPstB resulted in an 87.5% protection against challenge with serotype 2 and 9 strains, suggesting a high level of cross-protection for serotypes 2 and 9. A lower protection rate (62.5%) was observed in mice challenged with the serotype 7 strain. These data demonstrate that PstB is a promising target antigen for development as a component of a universal subunit vaccine against multiple serotypes.