Salmonella Vaccines Against Bacterial Enteropathogens

针对细菌性肠病原体的沙门氏菌疫苗

• 批准号: 8604123
• 负责人: ROY CURTISS III
• 金额: $ 43.71万
• 依托单位: ARIZONA STATE UNIVERSITY-TEMPE CAMPUS
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-09-30 至 2016-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8604123
• 关键词: Animal Feed; Animals; Antigens; Attenuated; Bacteria; Biological Containment; Campylobacter jejuni; Cessation of life; Clinical; Clostridium difficile; Clostridium perfringens; Collection; Communicable Diseases; Cytolysis; Data; Developing Countries; Disease; Economics; Enteral; Environment; Equilibrium; Escherichia coli; Evaluation; Food; Food Chain; Food Contamination; Food Safety; Health; Health Benefit; Helicobacter pylori; Human; Immune response; Immunity; Immunization; Infection; Institutional Review Boards; Legal patent; Licensing; Life; Listeria monocytogenes; Livestock; Morbidity - disease rate; Mutation; Outcome; Pasteurella pseudotuberculosis; Performance; Personal Satisfaction; Phase I Clinical Trials; Prevalence; Productivity; Protocols documentation; Public Health; Quality of life; Recombinants; Research; Safety; Salmonella; Salmonella Vaccines; Salmonella enterica; Salmonella paratyphi; Salmonella typhi; Salmonella typhimurium; Seeds; Serotyping; Severities; Shigella; Smallpox Vaccine; Streptococcus pneumoniae; Surface Antigens; System; Systemic disease; Technology; UNESCO; UNICEF; United States National Institutes of Health; Vaccination; Vaccine Design; Vaccines; Vibrio cholerae; Water; Water Supply; Yersinia; Yersinia enterocolitica; attenuation; cost; design; design and construction; enteric pathogen; food shortage; immunogenicity; improved; in vivo; innovative technologies; mortality; nutrition; pathogen; preclinical efficacy; preclinical safety; prevent; public health relevance; research clinical testing; research study; vaccine candidate; vector

DESCRIPTION (provided by applicant): Of the global 57 million deaths each year, about 1.8 (WHO) to 2.2 (UNESCO) million are due to infections with enteric pathogens including Salmonella, Escherichia coli and Shigella sp., and other entero-pathogens such as Yersinia sp., Vibrio cholerae, Campylobacter jejuni, Helicobacter pylori, Listeria monocytogenes, Clostridium perfringens and C. difficile. These pathogens are responsible for significant morbidity and are transmitted to humans by contaminated food and water. In developing countries, bacterial enteropathogens in food animals are major factors that decrease productivity of livestock creating food shortages and under-nourishment in humans. We believe 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. We therefore spent much effort to devise new improved means to construct recombinant attenuated Salmonella vaccine vector systems for animals and humans that are capable of inducing cross-protective immunity to enteric pathogens and of delivering genus- or species-specific protective antigens to further enhance induction of immunity to enteric pathogens. We propose to use these technologies to develop vaccines to prevent/reduce diarrheal diseases caused by bacterial enteropathogens in agriculturally important animals and humans. Our objectives include to: (i) complete construction of S. Typhimurium and S. Paratyphi A strains with regulated delayed attenuation attributes to expose and display cross-protective surface antigens, that minimize induction of immune responses to serotype-specific antigens, that possess mutations to enhance safety and immunogenicity, that can delivery multiple genus- and species-specific protective antigens and that display biological containment to preclude persistence in vivo or survival if excreted, (ii) complete construction of multiple vector systems using balanced-lethal, balanced-attenuation and regulated-lysis vector systems to maximize induction of protective immune responses by delivery of conserved protective antigens of Shigella, Yersinia, E. coli, C. jejuni and C. perfringens, (iii) conduct studies to evaluate (a) how best to maximize induction of cross-protective immunity, (b) ability to induce protective immunity against specific enteric pathogens, (c) consequences of vaccination on normal flora, (d) efficacy of mixtures of vaccines to protect against Salmonella and one or two other species versus a vaccine to protect against multiple enteric bacterial pathogens, and (e) means to experimentally validate a vaccine for humans to protect against multiple pathogens, and (iv) conduct studies to provide preclinical safety and efficacy data to satisfy APHIS for veterinary vaccines and FDA for human vaccines. We will annually amend our Master File, prepare and fully characterize candidate vaccine Master Seeds for stability and safety, prepare and submit protocols for IRB approvals, and submit information to facilitate conduct of clinical animal and human trials. We plan to ultimately develop vaccines to confer protection against V. cholerae, C. difficile, L. monocytogenes and H. pylori.

描述（由申请人提供）：全球每年有 5700 万人死亡，其中约 1.8（世界卫生组织）至 2.2（联合国教科文组织）死亡人数是由于肠道病原体感染造成的，包括沙门氏菌、大肠杆菌和志贺氏菌，以及其他肠道病原体，例如沙门氏菌、大肠杆菌和志贺氏菌。如耶尔森菌、霍乱弧菌、空肠弯曲杆菌、幽门螺杆菌、单核细胞增生李斯特菌、产气荚膜梭菌和艰难梭菌。这些病原体导致严重发病，并通过受污染的食物和水传播给人类。在发展中国家，食用动物体内的细菌性肠道病原体是降低牲畜生产力、造成人类粮食短缺和营养不良的主要因素。我们相信，改善健康、营养和经济福祉（后者依赖于前两者）是提高全球生活质量的最佳途径。因此，我们花费了大量精力设计新的改进方法，为动物和人类构建重组减毒沙门氏菌疫苗载体系统，该系统能够诱导对肠道病原体的交叉保护性免疫，并提供属或种特异性保护性抗原，以进一步增强诱导对肠道病原体的免疫力。我们建议利用这些技术开发疫苗，以预防/减少农业重要动物和人类中细菌性肠病原体引起的腹泻疾病。我们的目标包括：(i) 完成具有受控延迟减毒属性的鼠伤寒沙门氏菌和甲型副伤寒沙门氏菌菌株的构建，以暴露和展示交叉保护性表面抗原，从而最大限度地减少对具有突变的血清型特异性抗原的免疫反应的诱导为了增强安全性和免疫原性，可以递送多种属和种特异性保护性抗原，并表现出生物遏制性，以防止体内持久性或排泄后的存活，（ii）完整构建多个载体系统使用平衡致死、平衡减毒和调节裂解载体系统，通过递送志贺氏菌、耶尔森氏菌、大肠杆菌、空肠弯曲菌和产气荚膜梭菌的保守保护性抗原，最大限度地诱导保护性免疫反应，(iii) 进行研究评估（a）如何最好地诱导交叉保护性免疫，（b）诱导针对特定肠道病原体的保护性免疫的能力，（c）疫苗接种对正常菌群的影响，（d）混合物的功效预防沙门氏菌和一种或两种其他物种的疫苗与预防多种肠道细菌病原体的疫苗的比较，以及（e）通过实验验证人类疫苗预防多种病原体的方法，以及（iv）进行研究以提供临床前数据安全性和有效性数据，以满足兽用疫苗 APHIS 和人用疫苗 FDA 的要求。我们将每年修改我们的主文件，准备并充分描述候选疫苗主种子的稳定性和安全性，准备和提交方案以供 IRB 批准，并提交信息以促进临床动物和人体试验的进行。我们计划最终开发疫苗，以提供针对霍乱弧菌、艰难梭菌、单核细胞增生李斯特菌和幽门螺杆菌的保护。