A broadly protective subunit vaccine against enterotoxigenic Escherichia coli (ETEC) associateddiarrhea

一种针对产肠毒素大肠杆菌 (ETEC) 相关腹泻的广泛保护性亚单位疫苗

基本信息

批准号：
9912501
负责人：
WEIPING ZHANG
金额：
$ 43.66万
依托单位：
UNIVERSITY OF ILLINOIS AT URBANA-CHAMPAIGN
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-05-26 至 2021-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9912501
关键词：
Adult Animal Model Antibodies Antigens Antitoxins Bacteria Bacterial Adhesins Bacterial Attachment Site Bangladesh Cause of Death Cessation of life Child Data Developing Countries Development Diarrhea Disease Dose Enterotoxins Escherichia coli Adhesins Escherichia coli Vaccines Family suidae Genes Genetic Goals Heterogeneity Homeostasis Human Human Volunteers Immunity Immunize Immunologics International Intestines Kansas Laboratories Liquid substance Mediating Methods Modeling Morbidity - disease rate Oryctolagus cuniculus Outcome Prevention Preventive Preventive measure Production Proteins Public Health Recombinant Proteins Recombinants Research Sanitation Small Intestines Subunit Vaccines Toxic effect Toxin Toxoids Traveler&apos s diarrhea Universities Vaccination Vaccines Virulence Virulence Factors Virulent Work diarrheal disease enterotoxigenic Escherichia coli experience global health immunogenicity improved innovation international center mortality neutralizing antibody novel prevent protective efficacy receptor success vaccine candidate vaccine development vaccine efficacy

项目摘要

Project Summary: Diarrhea is the second leading cause of death in children <5 years, and remains a major public health problem. Enterotoxigenic Escherichia coli (ETEC), the most common bacterial cause of diarrhea, causes 280 to 400 million diarrheal cases in children <5 years and 100 million more cases in children >5 years annually, resulting in 150,000 to 300,000 deaths annually. ETEC also commonly cause travellers’ diarrhea. While improved sanitation is the eventual solution, vaccination will be the best preventive measure for many decades. Key virulence factors of ETEC are bacterial adhesins and enterotoxins. Adhesins mediate bacterial attachment to host receptors and colonization in small intestines. Enterotoxins, heat-labile toxin (LT) and heat- stable toxin (STa), disrupt intestinal fluid homeostasis to cause fluid hyper-secretion and diarrhea. A vaccine preventing bacteria colonization and neutralizing toxin enterotoxicity could effectively prevent ETEC diarrhea, but until now, a safe and effective ETEC vaccine has not been developed. Developing ETEC vaccines is challenging since the heterogeneous ETEC strains express at least 23 adhesins and 2 distinct toxins. As ETEC strains producing any one or two adhesins and either toxin (LT or STa) cause diarrhea, ideally, an effective ETEC vaccine should protect against all adhesins and both toxins. But protecting against 23 adhesins is not feasible and protecting against 2 toxins is very difficult. Additionally, suitable animal models to unambiguously assess efficacy of ETEC vaccine candidates have been lacking. In this study, we will develop a safe and broadly protective ETEC vaccine. We will apply a multiepitope fusion antigen (MEFA) method to create an adhesin MEFA to induce antibodies against the 7 key adhesins associates with 80% of ETEC diarrhea cases (caused by ETEC strains with known adhesins), and fuse an LT toxoid and a STa toxoid for a safe toxoid fusion to induce antibodies neutralizing both toxins. The adhesin MEFA and the toxoid fusion will be combined (co-administration) or further fused together (as a CFA-toxoid MEFA) to induce broadly protective anti-adhesin and antitoxin antibodies. We will then use a novel piglet and rabbit dual-challenge model to assess efficacy of a subunit vaccine candidate against ETEC diarrhea. Our preliminary studies show LT-STa toxoid fusions, adhesin MEFA and adhesin-toxoid fusion induce antibodies neutralizing both toxins and 7 adhesins and protecting pigs against ETEC diarrhea, and rabbits and pigs are ideal animal models for ETEC vaccine efficacy assessment. A broadly protective subunit ETEC vaccine will benefit millions of children and travelers. The innovative approaches developed in this research can be generally applied to multivalent vaccine development against other diseases.

项目摘要：腹泻是儿童<5岁的第二大死亡原因，仍然是主要的公共卫生问题。肠毒素大肠杆菌（ETEC），腹泻的最常见细菌，在儿童<5岁的儿童中导致280至4亿次腹泻病例，儿童多1亿例> 5岁独一无二的，每年150,000至300,000人死亡。 ETEC通常还会引起旅行者的腹泻。虽然改善的卫生是最终的解决方案，但疫苗接种将是许多人的最佳预防测量几十年。 ETEC的关键病毒因子是细菌粘附素和肠毒素。粘附素介导细菌对宿主受体的附着和小肠中的定殖。肠毒素，热法毒素（LT）和热 - 稳定的毒素（STA），破坏肠液稳态导致液体过度分泌和腹泻。疫苗防止细菌定植和中和毒素肠毒性可以有效预防EDEC腹泻，但是到目前为止，尚未开发安全有效的ETEC疫苗。开发ETEC疫苗是具有挑战性的，因为异质ETEC菌株至少表达23 胶粘剂和2种不同的毒素。作为ETEC条纹产生任何一种或两种粘合剂和毒素（LT或 sta）理想情况下，有效的ETEC疫苗应预防所有粘附和两种毒素。但是，防止23种粘附是不可行的，并且很难防止2种毒素。此外，缺乏明确评估ETEC疫苗候选物效率的合适动物模型。在这项研究中，我们将开发一种安全且广泛保护的ETEC疫苗。我们将应用一个多人融合抗原（MEFA）方法，可以创建一种粘合剂MEFA，以诱导7个关键粘合剂抗体与80％的ETEC腹泻病例（由具有已知粘附素的ETEC菌株引起的）和LT融合毒素和STA毒素，用于安全的毒素融合，诱导中和两种毒素的抗体。粘合剂 MEFA和毒素融合将组合（共同给药）或进一步融合在一起（作为CFA毒素 MEFA）诱导广泛保护的抗粘合剂和抗毒素抗体。然后，我们将使用一只新颖的小猪兔双挑战模型，以评估针对ETEC腹泻的亚基疫苗的效率。我们的初步研究表明，LT-STA毒素融合，粘附素MEFA和粘附蛋白毒素融合诱导抗体中和毒素和7种粘附剂，并保护猪免受Etec腹泻，兔子和猪是ETEC疫苗效率评估的理想动物模型。广泛保护的亚基ETEC疫苗将使数百万儿童和旅行者受益。创新这项研究中开发的方法通常可以应用于多价疫苗开发其他疾病。