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：
8700107
负责人：
WEIPING ZHANG
金额：
$ 18.75万
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 2016-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8700107
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 public health relevance 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）：国家卫生研究院（NIH）列出了腹泻大肠杆菌菌株B病原体的优先级。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）报告说，每年ETEC菌株会给儿童造成380-5亿个腹泻病例，成人旅行者增加4亿例病例，每年造成约30万-500,000人死亡。对于谁和其他全球和区域卫生计划来说，它是针对与ETEC相关的旅行者腹泻开发广泛保护性疫苗的重中之重。目前，尚无有效的疫苗来防止旅行者的腹泻。毒力决定因素腹泻的ETEC是细菌粘附素和肠毒素。粘合剂介导细菌的附着和小肠定植。肠毒素破坏宿主上皮细胞中的液体稳态，导致液体过度分泌和腹泻。诱导抗粘合剂免疫可阻止ETEC附着和定殖的疫苗以及抗毒素免疫以中和肠毒性可以有效地预防ETEC Traveler的腹泻。我们的长期目标是了解腹泻疾病的分子发病机理并制定预防疾病策略。我们的直接目标是开发针对ETEC腹泻的广泛保护性疫苗。我们在这里介绍了初步数据，显示：1）具有7种粘附素的代表性表位的多孔ETEC CFA抗原引起了广泛的保护性免疫反应； 2）LT和STA毒素融合抗原引起对两种毒素的中和抗体； 3）猪型CFA毒素融合诱导的抗异质粘附和毒素的保护性免疫。这项拟议研究的特定假设是：1）多尖CFA-毒素抗原将诱导对7种粘附素的广泛免疫反应，并由最普遍，最具毒性的ETEC菌株以及对LT和STA毒素的粘附素表达。 2）这种多尖的CFA毒剂抗原诱导的免疫力将防止表达这7种粘附素的ETEC菌株的粘附，并且也对ETEC毒素进行了中和，并且这种多孔CFA-Toxoid Fusion抗原可以作为抗Etec Traveler's diacrrrrrrrhea的亚基疫苗而形成。使用创新的策略来构建CFA毒素融合，小鼠免疫研究和新的小猪挑战研究，提出了以下具体目的来检验我们的假设：1）构建多尖的CFA CFA-TOXOXOID抗原，以抗7 ETEC粘附素的免疫力和毒素； 2）评估该多尖CFA-Toxin抗原的亚基疫苗候选物，以抗ETEC Traveler的腹泻。这项研究的结果将改变当前的ETEC疫苗发育策略，其中多个杀死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。已经显示出产品中的多种菌株会导致免疫反应较低（没有明显的保护），并且由于产品中包含的过量体细胞抗原和LP而引起不良反应。表达最普遍，最具毒性的ETEC粘附素和两种毒素的抗原表位，可以导致安全有效的亚基疫苗，以防止对旅行者的腹泻进行广泛的保护。