New Approaches to optimize Salmonella Enterica Serovar Typhimurium Strains as Tools for Vaccination & Immunotherapy

Vaccination is currently considered as the most efficient approach to combat infectious diseases. In addition to preventive vaccination, therapeutic vaccination may be used to treat infectious diseases and non-infectious diseases such as cancer. For this strategy, Salmonella enterica serotypes Typhimurium and Typhi are suitable organisms for the generation of live recombinant vaccines. Genetic manipulation allows the generation of attenuated strains that are safe for application in vaccinees and the introduction of heterologous antigens. Attenuated Salmonella strain can stimulate mucosal as well as systemic immunity against the carrier itself or coexpressed heterologous antigens. In addition to the use as carriers for vaccination against various bacterial, viral or parasitic infections, Salmonella strains can also be used for production of cytokines or as tumor-targeting agents.This study was directed to analyze the immune response to Salmonella carrier strains expressing model antigens using novel detection methods. Furthermore, currently available combinations of strains and vectors were optimized for stability.Various systems have been developed for the expression of heterologous antigens by attenuated Salmonella carrier strains. In general, these systems require stabilization of the expression of the heterologous antigens. We show that expression of heterologous antigens in Salmonella under control of regulated promoters stimulate superior immune responses compared to similar strains that express the same antigens from constitutive promoters.The potential use as vaccine delivery system of S. Typhimurium strain harboring defined mutation in the sseC (HH 104) gene, which encode putative effector proteins of the type III secretion system of 5P12, was evaluated and compared with that of the well-characterized aroA mutant strain SL7207 by using OVA as a model antigen. When orally administered to BALB/c mice, both mutants were found to be highly attenuated. Both strains were also able to efficiently colonize and persist in Peyer’s patches. Immunization with HHIO4 triggered OVA-specific serum and mucosal antibody responses stronger than those observed in SL7207-immunized mice. Here, attenuated Salmonella enterica serovar Typhimurium SL7207 and Salmonella enterica serovar Typhimurium HH1O4 strains expressing the model antigen OVA were used to quantify in vivo antigen levels by flow cytometry, whereas antigen-specific T-cell responses in mice that are transgenic for a T-cell receptor recognizing OVA. Furthermore, we demonstrated that recombinant S.