The nature of the attenuation of Salmonella typhimurium strains expressinghuman papillomavirus type 16 virus-like particles determines the systemic and mucosal antibody responses in nasally immunized mice

We have recently shown by using a recombinant Salmonella typhimurium PhoP(c ) strain in mice the feasibility of using a Salmonella-based vaccine to pre vent infection by the genital human papillomavirus type 16 (HPV16). Here, w e compare the HPV16-specific antibody responses elicited by nasal immunizat ion with recombinant S. typhimurium strains harboring attenuations that, in contrast to PhoPc, are suitable for human use. For this purpose, chi 4989 (Delta cya Delta crp) and chi 4990 [Delta cya Delta(crp-cdt)] were construc ted in the ATCC 14028 genetic background, and comparison was made with the isogenic PhoP(c) and PhoP(-) strains. Although the levels of expression of HPV16 virus-like particle (VLP) were similar in all strains, only PhoP(c) H PV16 induced sustained specific antibody responses after nasal immunization , while all strains induced high antibody responses with a single nasal imm unization when an unrelated viral hepatitis B core antigen was expressed. T he level of the specific antibody responses induced did not correlate with the number of recombinant bacteria surviving in various organs 2 weeks afte r immunization. Our data suggest that the immunogenicity of attenuated Salm onella vaccine strains does not correlate with either the number of persist ing bacteria after immunization or the levels of in vitro expression of the antigen carried. Rather, the PhoP(c) phenotype appears to provide the uniq ue ability in Salmonella to induce immune responses against HPV16 VLPs.