Development of a new vaccine against Plague

About Although an effort towards vaccination is ongoing, no efficient and safe vaccine against plague is currently available. During the last decade, we developed a new vaccine against plague. The project was funded by a series of grants (Ministry of Research, Pasteur Institute, NRBC program via CEA, National Research Agency-ANR, DGA). Our live attenuated oral vaccine is based on Y. pseudotuberculosis, the ancestor of Y. pestis with which it is genetically almost identical, although much less virulent and genetically more stable. We first demonstrated that a Y. pseudotuberculosis could be used by means of a naturally avirulent strain form our collection, but then constructed a genetically defined strain by modifying a Y. pseudotuberculosis which genome was fully sequenced. This new plague vaccine candidate, named VTnF1, was constructed by deleting the genes for three essential virulence factors from the strain IP32953, the first whose genome was known. In addition, the operon encoding the highly immunogenic Y. pestis F1 pseudocapsule antigen was inserted in the chromosome to induce the production of the highly protective F1 antigen, an abundant surface signature of the plague bacillus that elicits a protective antibody response. The absence of pathogenicity of this new vaccine and its ability to induce a good humoral and cellular response against Y. pestis have been demonstrated. More recently, a strain without antibiotic resistance cassettes has been reconstructed. By the oral route, natural to Y. pseudotuberculosis, VTnF1 protects mice 100% against lethal pneumonic plague caused by 3000 times the median lethal dose (MLD) of Y. pestis. VTnF1 also protects 100% against bubonic plague, up to 10000 DML. The worst bioterror threat using plague would be an attack with infectious aerosols, to cause highly contagious and rapidly fatal pneumonic plague. An F1-negative Y. pestis, as a potential bacteriological threat, would then be undetectable by common tests and resistant to F1 immunity. In mice, our VTnF1 vaccine confers protection against this type of infection. This long-term project benefits from the support of the "Direction des Vaccines" of the Institut Pasteur.