Our long-term goals are directed at developing recombinant avirulent Salmonella vaccines for oral administration to protect humans against bacterial, viral, mycotic and parasitic pathogens, especially those that colonize on or invade through mucosal surfaces. Toward this goal, we propose to expand the host-vector options for such recombinant vaccines in order to circumvent potential difficulties with repeat immunizations for one or several different recombinant avirulent Salmonella vaccines. The objectives of the research to be conducted during the phase I study include: 1) to introduce genetically defined chromosome deletion mutations that are known to render S. typhimurium and S. typhi avirulent and immunogenic in mice and humans, respectively, into Salmonella paratyphi A, S. paratyphi B (S. shottmuellerii) and S. paratyphi C (S. herschfeldii), and 2) to characterize these strains in comparison to S. typhimurium and S. typhi constructs for stability of mutant phenotype, growth rate, ability to attach to, invade, multiply in and transcytose cells in culture, and for avirulence and immunogenicity in mice. The objective during the phase II study will be to evaluate avirulence and immunogenicity of the S. paratyphi mutants in humans and to investigate utility as the host-vector component of recombinant vaccines to stimulate, following oral immunization, mucosal, humoral and cellular immunities.
