S. typhimiurium Vaccine Against Bacterial Enteropathogens

在每年1,890万宗因传染病而死亡的个案中，约有200万宗是由沙门氏菌和其他相关的肠道病原体(包括大肠杆菌和志贺氏菌)，以及与之关系不大的肠道病原体如霍乱弧菌、空肠弯曲杆菌和单核细胞增生性李斯特氏菌感染所致。此外，这些细菌对引起腹泻和系统性疾病的重大发病率负有责任，这些疾病可以通过污染食品和/或供水传播给人类，这种污染可能是故意的。我们相信，改善健康、营养和经济福祉(后者取决于前两者)是提高全球生活质量、从而减少导致战争和恐怖行为的条件的最佳手段，我们基于我们在使用非重组和重组减毒沙门氏菌兽用疫苗预防和减少细菌肠道病原体引起的腹泻疾病方面的最新技术发展，提出了一个疫苗开发计划。我们的目标包括：(I)进一步对一株鼠伤寒沙门氏菌进行基因改造，以最大限度地减少对血清型特异性抗原的免疫反应，并最大限度地诱导对不同血清型肠出血性沙门氏菌共同相关抗原的交叉保护性免疫，然后全面评估该改良株作为疫苗，以减少由肠溶血性沙门氏菌血清型和可能由其他细菌肠道病原体引起的人类腹泻疾病，特别是EPEC、ETEC和EHEC类型的大肠杆菌和志贺氏菌；(Ii)设计、建造和全面评估一种甲型副伤寒沙门氏菌的减毒衍生物，其遗传特性与为同一目的而设计的鼠伤寒沙门氏菌疫苗相似，以诱导人体产生交叉保护免疫，以预防肠热病和显著减少因感染不同的肠杆菌血清型和可能由其他细菌性肠道病原体(尤其是EPEC、ETEC和EHEC类型的大肠杆菌和志贺氏菌)感染而引起的腹泻疾病；(Iii)进一步对旨在诱导交叉保护免疫的鼠伤寒沙门氏菌和甲型副伤寒沙门氏菌疫苗进行基因改造，使其也显示生物包容，使其不能在肠道或自然界中生存和/或在接种给免疫个体后约10个细胞分裂后因裂解而死亡；及(Iv)设计、构建和评估重组减毒沙门氏菌疫苗，利用免疫原性、生物包容和抗原输送的最佳属性，表达抗原，以进一步增强对与沙门氏菌相关的细菌肠道病原体的交叉保护免疫诱导，或对与沙门氏菌相关的肠道病原体之一授予保护性免疫。 我们还将协力开发我们的主文件，准备和全面描述候选疫苗主种子的稳定性和安全性，准备和提交IRB批准的方案，提交获得IND所需的信息，并执行安排最佳候选疫苗在人类志愿者中进行临床评估所需的任何其他工作。

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.