Yersinia pestis, the agent of
plague, is among the deadliest bacterial pathogens affecting humans, and is a potential
biological weapon. Because
antibiotic resistant strains of Yersinia pestis have been observed or could be engineered for evil use, vaccination against
plague might become the only means to reduce mortality. Although
plague is re-emerging in many countries, a
vaccine with worldwide license is currently lacking. The
vaccine strategy described here is based on an oral vaccination with an attenuated strain of Yersinia pseudotuberculosis. Indeed, this species is genetically almost identical to Y. pestis, but has a much lower pathogenicity and a higher
genomic stability. Gradual modifications of the wild-type Yersinia pseudotuberculosis strain IP32953 were performed to generate a safe and immunogenic
vaccine. Genes coding for three essential
virulence factors were deleted from this strain. To increase cross-species immunogenicity, an F1-encapsulated Y. pseudotuberculosis strain was then generated. For this, the Y. pestis caf operon, which encodes F1, was inserted first on a plasmid, and subsequently into the chromosome. The successive steps achieved to reach maximal
vaccine potential are described, and how each step affected bacterial virulence and the development of a protective immune response is discussed. The final version of the
vaccine, named VTnF1, provides a highly efficient and long-lasting protection against both bubonic and
pneumonic plague after a single oral
vaccine dose. Since a Y. pestis strain deprived of F1 exist or could be engineered, we also analyzed the protection conferred by the
vaccine against such strain and found that it also confers full protection against the two forms of
plague. Thus, the properties of VTnF1 makes it one of the most efficient candidate
vaccine for mass vaccination in tropical endemic areas as well as for populations exposed to bioterrorism.