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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）是旅行者腹泻最常见的原因。世界卫生组织（世卫组织）报告说，ETEC菌株每年造成3.8亿至5亿儿童腹泻病例，4亿成人旅行者腹泻病例，每年造成约30万至50万人死亡。世卫组织以及其他全球和区域卫生项目的首要任务是开发一种具有广泛保护性的疫苗，以预防与大肠杆菌相关的旅行者腹泻。目前，还没有有效的疫苗来预防旅行者腹泻。的毒力决定因素