A subunit vaccine for enterotoxigenic E. coli associated traveler's diarrhea

一种针对产肠毒素大肠杆菌相关旅行者腹泻的亚单位疫苗

基本信息

批准号：
8838707
负责人：
WEIPING ZHANG
金额：
$ 22.5万
依托单位：
KANSAS STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-04-15 至 2017-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8838707
关键词：
Adherence Adult Adverse effects Antibodies Antigens Antitoxins Bacteria Bacterial Adhesins Categories Cells Cessation of life Child Chimeric Proteins Communicable Diseases Data Development Diarrhea Disease Elements Enterotoxins Epithelial Cells Epitopes Escherichia coli Escherichia coli Adhesins Escherichia coli Infections Escherichia coli Vaccines Family suidae Feces Genetic Goals Health Heating Homeostasis Immune response Immunity Immunization Institutes Lead Life Liquid substance Mediating Modeling Molecular Mus Outcome Pathogenesis Prevention strategy Protein Subunits Recombinants Reporting Serum Small Intestines Subunit Vaccines Testing Toxin Toxoids Traveler&apos s diarrhea United States National Institutes of Health Vaccines Virulence Virulent World Health Organization disorder prevention enterotoxigenic Escherichia coli innovation killings neutralizing antibody novel pathogen prevent programs protective efficacy vaccine candidate vaccine development

项目摘要

DESCRIPTION (provided by applicant): Diarrheal E. coli strains are listed the priority category B pathogen by the National Institute of Health (NIH). Enterotoxigenic Escherichia coli (ETEC) are the most common cause of traveler's diarrhea. The World Health Organization (WHO) reported that each year ETEC strains cause 380-500 million diarrhea cases to children and 400 million more cases to adult travelers, which results in approximately 300,000- 500,000 deaths annually. It is a top priority for WHO and other global and regional health programs to develop a broadly protective vaccine against ETEC-associated traveler's diarrhea. Currently, there are no effective vaccines available to protect against traveler's diarrhea. The virulence determinants of ETEC in diarrhea are bacterial adhesins and enterotoxins. Adhesins mediate bacteria attachment and colonization at small intestines. Enterotoxins disrupt fluid homeostasis in host epithelial cells that leads to fluid hyper-secretion and diarrhea. A vaccine inducing anti-adhesin immunity to block ETEC attachment and colonization and also antitoxin immunity to neutralize enterotoxicity can effectively protect against ETEC traveler's diarrhea. Our long-term goal is to understand molecular pathogenesis of diarrhea diseases and to develop disease prevention strategies. Our immediate objective is to develop a broadly protective vaccine against ETEC diarrhea. We here present preliminary data showing that: 1) a multiepitope ETEC CFA antigen carrying representative epitopes of 7 adhesins induced broadly protective immune responses; 2) LT and STa toxoid fusion antigens elicited neutralizing antibodies against both toxins; and 3) a porcine-type CFA-toxoid fusion induced protective immunity against heterogeneous adhesins and also the toxin. The specific hypotheses for this proposed study are that: 1) a multiepitope CFA- toxoid antigen will induce broad immune responses to 7 adhesins expressed by the most prevalent and most virulent ETEC strains and also to both LT and STa toxins; and 2) immunity induced by this multiepitope CFA-toxoid antigen will protect against adherence of ETEC strains expressing these 7 adhesins and also neutralize against both ETEC toxins, and this multiepitope CFA-toxoid fusion antigen can be developed as a subunit vaccine against ETEC traveler's diarrhea. Using innovative strategies to construct a CFA-toxoid fusion, mouse immunization studies and a novel piglet challenge study, the following specific aims are proposed to test our hypothesis: 1) To construct a multiepitope CFA-toxoid antigen for immunity against 7 ETEC adhesins and both toxins; 2) To evaluate this multiepitope CFA-toxin antigen for subunit vaccine candidacy against ETEC traveler's diarrhea. Results from this study will change current ETEC vaccine development strategies, of which multiple killed or live E. coli strains and recombinant toxin subunit protein are mixed together to induce anti-adhesin immunity. Mixing multiple strains in a product has been shown to result in lower immune responses (with no significant protection) and to cause adverse effects due to excessive somatic antigens and LPS included in products. Expressing antigenic epitopes of the most prevalent and virulent ETEC adhesins and both toxins as a single antigen can lead to a safe and effective subunit vaccine for broad protection against traveler's diarrhea.

描述（由申请人提供）：腹泻大肠杆菌菌株被美国国立卫生研究院 (NIH) 列为优先 B 类病原体。产肠毒素大肠杆菌 (ETEC) 是旅行者腹泻的最常见原因。世界卫生组织 (WHO) 报告称，ETEC 菌株每年导致 380-5 亿例儿童腹泻病例和 4 亿例成人旅行者腹泻病例，每年导致约 300,000-500,000 人死亡。开发针对 ETEC 相关旅行者腹泻的广泛保护性疫苗是世卫组织和其他全球和区域卫生规划的首要任务。目前，没有有效的疫苗可以预防旅行者腹泻。毒力决定因素腹泻中的 ETEC 是细菌粘附素和肠毒素。粘附素介导细菌在小肠的附着和定植。肠毒素破坏宿主上皮细胞中的液体稳态，导致液体分泌过多和腹泻。诱导抗粘附素免疫以阻止 ETEC 附着和定植以及抗毒素免疫以中和肠毒性的疫苗可以有效预防 ETEC 旅行者腹泻。我们的长期目标是了解腹泻疾病的分子发病机制并制定疾病预防策略。我们的近期目标是开发一种针对 ETEC 腹泻的广泛保护性疫苗。我们在这里提供的初步数据表明：1）携带 7 个粘附素代表性表位的多表位 ETEC CFA 抗原诱导广泛的保护性免疫反应； 2) LT 和 STa 类毒素融合抗原引发针对这两种毒素的中和抗体； 3)猪型CFA-类毒素融合物诱导针对异源粘附素和毒素的保护性免疫。本研究的具体假设是： 1) 多表位 CFA 类毒素抗原将诱导针对最流行和最具毒性的 ETEC 菌株表达的 7 种粘附素以及 LT 和 STa 毒素的广泛免疫反应； 2) 这种多表位 CFA-类毒素抗原诱导的免疫将防止表达这 7 种粘附素的 ETEC 菌株的粘附，并且中和两种 ETEC 毒素，并且这种多表位 CFA-类毒素融合抗原可以开发为针对 ETEC 旅行者腹泻的亚单位疫苗。使用创新策略构建 CFA-类毒素融合、小鼠免疫研究和新型仔猪激发研究，提出以下具体目标来检验我们的假设： 1) 构建多表位 CFA-类毒素抗原，用于针对 7 种 ETEC 粘附素和两者的免疫毒素； 2) 评估这种多表位 CFA 毒素抗原作为针对 ETEC 旅行者腹泻的亚单位疫苗的候选资格。这项研究的结果将改变目前的 ETEC 疫苗开发策略，其中将多种灭活或活的大肠杆菌菌株和重组毒素亚基蛋白混合在一起以诱导抗粘附素免疫。在产品中混合多种菌株已被证明会导致免疫反应降低（没有显着的保护作用），并且由于产品中含有过多的体细胞抗原和脂多糖而导致不利影响。将最流行和最具毒性的 ETEC 粘附素和两种毒素的抗原表位表达为单一抗原，可以产生安全有效的亚单位疫苗，广泛预防旅行者腹泻。