Orally administered recombinant attenuated Salmonella vaccines (RASVs) elicit humoral and mucosal immune responses against the immunizing antigen. The challenge in developing an effective vaccine against a virus or an intracellular bacterium delivered by RASVs is to introduce the protective antigen inside the host cell cytoplasm for presentation to MHC-I molecules for an efficient cell mediated immune response. To target the influenza nucleoprotein (NP) into the host cell cytosol, we constructed a regulated delayed lysis in vivo RASV strain χ11246(pYA4858) encoding influenza NP with a chromosomal deletion of the sifA gene to enable it to escape from the endosome prior to lysis. Oral immunization of mice with χ11246(pYA4858) (SifA⁻) with 3 booster immunizations resulted in complete protection (100%) against a lethal influenza virus (rWSN) challenge (100 LD₅₀) compared to 25% survival of mice immunized with the isogenic χ11017(pYA4858) (SifA⁺) strain. Reducing the number of booster immunizations with χ11246(pYA4858) from 3 to 2 resulted in 66% survival of mice challenged with rWSN (100 LD₅₀). Immunization with χ11246(pYA4858) via different routes provided protection in 80% orally, 100% intranasally and 100% intraperitoneally immunized mice against rWSN (100 LD₅₀). A Th1 type immune response was elicited against influenza NP in all experiments. IFN-γ secreting NP₁₄₇₋₁₅₅ specific T cells were not found to be correlated with protection. The role of antigen-specific CD8⁺ T cells remains to be determined. To conclude, we showed that Salmonella can be designed to deliver antigen(s) to the host cell cytosol for presumably class I presentation for the induction of protective immune responses.
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