Abstract
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.
Highlights
Enteric fever is a communicable and foodborne disease accounting for a global incidence of 26.9 million each year, and remains a serious public health issue in many developing countries (Buckle et al, 2012)
Enteric fever is predominantly caused by the human restricted pathogens Salmonella enterica serovar Typhi and S
The entire viaB locus (∼13.9 kb), which contains 10 genes accounting for the Vi synthesis and export, as well as the tviA promoter, was amplified by PCR with a high fidelity DNA polymerase, and inserted into pSTV28 creating pSTV28viaB
Summary
Enteric fever is a communicable and foodborne disease accounting for a global incidence of 26.9 million each year, and remains a serious public health issue in many developing countries (Buckle et al, 2012). Enteric fever is predominantly caused by the human restricted pathogens Salmonella enterica serovar Typhi and S. Paratyphi A (Crump and Mintz, 2010). Paratyphi A-caused enteric fever has remarkably increased, in some areas of Asia (Ochiai et al, 2005; Crump and Mintz, 2010; Sahastrabuddhe et al, 2013; Waddington et al, 2014). Paratyphi A infection (Sahastrabuddhe et al, 2013). Paratyphi A are largely overlapped (Crump and Mintz, 2010), a bivalent vaccine covering the two serovars is apparently a better choice than a monovalent vaccine in the control strategy of enteric fever
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