Salmonella Vaccines Against Bacterial Enteropathogens

针对细菌性肠病原体的沙门氏菌疫苗

• 批准号: 8417023
• 负责人: ROY CURTISS III
• 金额: $ 41.08万
• 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 2015-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8417023
• 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）：在每年全球5700万人死亡中，约1.8（WHO）至2.2（联合国教科文组织），是由于感染了包括沙门氏菌，大肠杆菌和志贺氏菌Sp。在内的肠道病原体的感染，以及其他肠道疾病，以及其他肠道病原体，例如Yersinia sp。，Yersinia sp。单核细胞增生，梭状芽胞杆菌和艰难梭菌。这些病原体导致了明显的发病率，并通过受污染的食物和水传播给人类。在发展中国家，食用动物中的细菌肠病是降低牲畜生产率的主要因素，从而造成人类的粮食短缺和营养不良。我们认为，改善健康，营养和经济福祉（后者取决于前两个）为增强全球生活质量提供了最佳手段。因此，我们花了很多努力来设计新的改进手段，以为动物和人类构建重组衰减的沙门氏菌疫苗媒介系统，这些动物和人类能够诱导对肠道病原体的交叉保护免疫，并提供属或物种特异性保护性抗原以进一步增强对肠道病原体的免疫力的诱导。我们建议使用这些技术开发疫苗，以预防/减少由细菌肠道病毒引起的腹泻疾病，这些疾病在农业重要的动物和人类中。我们的目标包括：（i）完全构造鼠伤寒链霉菌和副链球菌A菌株具有受调节的延迟衰减属性，可暴露和显示交叉保护的表面抗原，最小化对血清型特异性抗原的免疫反应，以增强对生物类路的群体和免疫基因，并具有生理性的特定型物质，并且可以增强其具有生理性的基因生成性，并可以增强属性的属性。 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最大化跨保护免疫力，（b）能够诱导对特定肠道病原体的保护性免疫力的能力，（c）疫苗接种对正常植物群的后果，（d）疫苗混合物保护疫苗的混合物的功效，以防止疫苗防止沙门氏菌和一种或两种疫苗，以防止多种肠子的疫苗，以防止疫苗的疫苗，并试用过疫苗的疫苗（EA）。病原体和（IV）进行研究以提供临床前的安全性和有效性数据，以满足兽医疫苗的垂直性和人类疫苗的FDA。我们每年将修改我们的主文件，准备并充分表征候选疫苗主种子以保持稳定性和安全性，为IRB批准准备和提交协议，并提交信息以促进临床动物和人类试验的行为。我们计划最终开发疫苗，以赋予霍乱，艰难梭菌，L。单核细胞增生菌和幽门螺杆菌的保护。