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Enteric fever is predominantly caused by  Salmonella enterica  serovar Typhi and  Salmonella enterica  serovar Paratyphi A, and accounts for an annual global incidence of 26.9 millions. In recent years, the rate of  S . Paratyphi A infection has progressively increased. Currently licensed vaccines for typhoid fever, live Ty21a vaccine, Vi subunit vaccine, and Vi-conjugate vaccine, confer inadequate cross immunoprotection against enteric fever caused by  S . Paratyphi A. Therefore, development of bivalent vaccines against enteric fever is urgently required. The immunogenic Vi capsular polysaccharide is characteristically produced in  S . Typhi, but it is absent in  S . Paratyphi A. We propose that engineering synthesis of Vi in  S . Paratyphi A live-attenuated vaccine may expand its protection range to cover  S . Typhi. In this study, we cloned the  viaB  locus, which contains 10 genes responsible for Vi biosynthesis, and integrated into the chromosome of  S . Paratyphi A CMCC 50093. Two virulence loci,  htrA  and  phoPQ , were subsequently deleted to achieve a Vi-producing attenuated vaccine candidate. Our data showed that, despite more than 200 passages, the  viaB  locus was stably maintained in the chromosome of  S . Paratyphi A and produced the Vi polysaccharide. Nasal immunization of the vaccine candidate stimulated high levels of Vi-specific and  S . Paratyphi A-specific antibodies in mice sera as well as total sIgA in intestinal contents, and showed significant protection against wild-type challenge of  S . Paratyphi A or  S . Typhi. Our study show that the Vi-producing attenuated  S . Paratyphi A is a promising bivalent vaccine candidate for the prevention of enteric fever.

frontiers in cellular and infection microbiology

Vi Capsular Polysaccharide Produced by Recombinant Salmonella enterica Serovar Paratyphi A Confers Immunoprotection against Infection by Salmonella enterica Serovar Typhi