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We hypothesized that the immunogenicity of live  Salmonella enterica  serovar Typhi vaccines expressing heterologous antigens depends, at least in part, on its  rpoS  status. As part of our project to develop a recombinant attenuated  S . Typhi vaccine (RASTyV) to prevent pneumococcal diseases in infants and children, we constructed three RASTyV strains synthesizing the  Streptococcus pneumoniae  surface protein PspA to test this hypothesis. Each vector strain carried ten engineered mutations designed to optimize safety and immunogenicity. Two  S . Typhi vector strains (χ9639 and χ9640) were derived from the  rpoS  mutant strain Ty2 and one (χ9633) from the RpoS +  strain ISP1820. In χ9640, the nonfunctional  rpoS  gene was replaced with the functional  rpoS  gene from ISP1820. Plasmid pYA4088, encoding a secreted form of PspA, was moved into the three vector strains. The resulting RASTyV strains were evaluated for safety  in vitro  and for immunogenicity in mice. All three RASTyV strains were similar to the live attenuated typhoid vaccine Ty21a in their ability to survive in human blood and human monocytes. They were more sensitive to complement and were less able to survive and persist in sewage and surface water than their wild-type counterparts. Adult mice intranasally immunized with any of the RASTyV strains developed immune responses against PspA and  Salmonella  antigens. The RpoS +  vaccines induced a balanced Th1/Th2 immune response while the RpoS −  strain χ9639(pYA4088) induced a strong Th2 immune response. Immunization with any RASTyV provided protection against  S. pneumoniae  challenge; the RpoS +  strain χ9640(pYA4088) provided significantly greater protection than the ISP1820 derivative, χ9633(pYA4088). In the pre-clinical setting, these strains exhibited a desirable balance between safety and immunogenicity and are currently being evaluated in a Phase 1 clinical trial to determine which of the three RASTyVs has the optimal safety and immunogenicity profile in human hosts.

Live Recombinant Salmonella Typhi Vaccines Constructed to Investigate the Role of rpoS in Eliciting Immunity to a Heterologous Antigen