S. typhimiurium Vaccine Against Bacterial Enteropathogens

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Of the 18.9 million annual deaths (1997) due to infectious diseases, about 2 million are the result of infections by Salmonella and other related bacterial enteropathogens including Escherichia coli and Shigella species, and less closely related enteropathogens such as Vibrio cholerae, Campylobacter jejuni and Listeria monocytogenes. In addition, these bacteria are responsible are responsible for significant morbidity causing diarrheal and systemic diseases that can be transmitted to humans by contamination of food products and/or the water supply and such contamination can be willful. In the belief that improving health, nutrition and economic well-being (the latter dependent on the first two) provide the best means to enhance the quality of life globally and thus reduce conditions that result in warlike and terrorist behavior, we propose a vaccine developmental program based on our recent technical developments in using non-recombinant and recombinant attenuated Salmonella veterinary vaccines to prevent-reduce diarrheal diseases caused by bacterial enteropathogens. Our objectives include: (i) to further genetically modify a strain of Salmonella typhimurium that has been designed to minimize induction of immune responses to serotype-specific antigens and to maximize induction of cross protective immunity to common related antigens of S. enterica strains of diverse serotype and then fully evaluate this modified strain as a vaccine to reduce diarrheal diseases in humans caused by S. enterica serotypes and possibly by other bacterial enteric pathogens, especially Escherichia coli of the EPEC, ETEC and EHEC types and Shigella; (ii) to design, construct and fully evaluate an attenuated derivative of S. paratyphi A, with similar genetic attributes as the S. typhimurium vaccine designed for the same purpose, to induce cross protective immunity in humans to prevent enteric fever and to significantly reduce diarrheal diseases due to infection by diverse S. enterica serotypes and possibly by other bacterial enteric pathogens, especially E. coli of the EPEC, ETEC and EHEC types and Shigella; (iii) to further genetically modify the S. typhimurium and S. paratyphi A vaccines designed to induce cross protective immunity to also display biological containment so that they are less able to survive in the intestinal tract or in nature and/or die by lysis after approximately ten cell divisions following delivery to the immunized individual; and (iv) to design, construct and evaluate recombinant attenuated Salmonella vaccines, using optimal attributes for immunogenicity, biological containment and antigen delivery, to express antigens to further enhance induction of cross protective immunity to Salmonella-related bacterial enteropathogens or to confer protective immunity to one of the less Salmonella-related enteropathogens. We will also collaboratively work to develop our Master File, prepare and fully characterize candidate vaccine Master Seeds for stability and safety, prepare and submit protocols for IRB approvals, submit information necessary to obtain INDs, and perform any other work needed to arrange that the best candidate vaccines by clinically evaluated in human volunteers.