Abstract
ABSTRACTSalmonella enterica serovar Paratyphi A is the main causative agent of paratyphoid fever in many Asian countries. As paratyphoid is spread by the fecal-oral route, the most effective means of controlling S. Paratyphi A infection is through the availability of clean water supplies and working sanitation services. Because sanitation facilities improve slowly in these poor areas and antibiotic resistance is severe, the development of a safe and effective vaccine remains a priority for controlling the spread of paratyphoid disease. In this study, we investigated the strategy of heterologous O-antigenic O2 serotype (S. Paratyphi A characterized) conversion in S. Typhimurium to prevent paratyphoid infections. A series of S. Typhimurium mutants were constructed with replacement of abe, wzxB1 and wbaVB1 genes with respective prt-tyvA1, wzxA1 and wbaVA1, and the results showed that only three genes including prt, wbaVA1 and wzxA1 from S. Paratyphi A presence enable S. Typhimurium to sufficiently express O2 antigen polysaccharide. We also constructed a series of live attenuated S. Typhimurium vaccine candidates expressing heterologous O2 O-antigens, and a mouse model was used to evaluate the immunogenicity of live vaccines. ELISA data showed that vaccine candidates could induce a comparatively high level of S. Paratyphi A and/or S. Typhimurium LPS-specific IgG and IgA responses in murine model, and IgG2a levels were consistently higher than IgG1 levels. Moreover, the functional properties of serum antibodies were evaluated using in vitro C3 complement deposition and opsonophagocytic assays. Our work highlights the potential for developing S. Typhimurium live vaccines against S. Paratyphi A.
Highlights
Typhimurium showed C3 complement deposition on their surface when incubated with sera from mice immunized with S738, S1112, S1151 and S1166. These results indicated that antibodies in the mice sera induced by live vaccine candidates were able to trigger the classical pathway of complement activation
As O-antigen portion of LPS is an essential virulence factor and a protective antigen, it has been speculated that antibody against the LPS of S
There is a bottleneck for oral paratyphoid vaccine development due to the lack of appropriate animal models for preclinical tests
Summary
The global burden of enteric fever is significant, with 21.6 million illnesses and 216,500 deaths reported in 2000 worldwide [2,3]. Typhi was believed to be a major cause of enteric fever. Typhi as the primary causative agent of enteric fever in many Asian countries [4,5,6,7]. Paratyphi A is through the availability of clean water supplies and working sanitation services. Considering that these infrastructures tend to improve slowly, the development of a safe and effective vaccine remains a good choice for controlling the spread of paratyphoid disease [6,7]
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