Rational live oral carrier vaccine design by mutating virulence-associated genes of Yersinia enterocolitica.

Three different Yersinia enterocolitica serotype O8 strains harboring mutations in virulence-associated genes coding for Yersinia adhesin A (YadA), Mn-cofactored superoxide dismutase (SodA), and high-molecular-weight protein 1 were analyzed for their ability to colonize and persist in tissues after orogastric immunization of C57BL/6 mice. We demonstrated that all three Yersinia mutant strains were markedly impaired in their ability to disseminate into the spleens and livers of immunized mice but were able to colonize the Peyer's patches for at least 12 days, resulting in the induction of significant antibody titers against Yersinia outer proteins (Yops) and in the priming of Yersinia antigen-specific CD4+ Th1 cells isolated from spleens. The high level of attenuation did not diminish the immunogenic properties of the mutant strains. In fact, mice immunized with a single oral dose of any of the mutant strains were protected against a lethal oral-challenge infection with wild-type Y. enterocolitica. Moreover, adoptive transfer of Yersinia-specific antibodies from sera of mice immunized with the mutant WAP-314 sodA revealed that this protection could be mediated by Yersinia-specific immunoglobulins.