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 5 岁以下儿童的第二大死因，并且仍然是一个主要死因产肠毒素大肠杆菌（ETEC）是引起腹泻的最常见细菌，导致 280 至 4 亿例 5 岁以下儿童腹泻病例，以及 1 亿例 5 岁以上儿童腹泻病例每年造成 150,000 至 300,000 人死亡，ETEC 通常也会导致旅行者腹泻。虽然改善卫生条件是最终的解决方案，但对于许多人来说，疫苗接种将是最好的预防措施几十年。 ETEC 的关键毒力因子是细菌粘附素和介导细菌的肠毒素。附着于宿主受体并在小肠中定植。稳定毒素 (STa)，破坏肠液稳态，导致液体分泌过多和腹泻。防止细菌定植，中和毒素肠毒性，可有效预防ETEC腹泻，但迄今为止，安全有效的ETEC疫苗尚未研发出来。开发 ETEC 疫苗具有挑战性，因为异质 ETEC 菌株表达至少 23 作为产生任何一种或两种粘附素和一种毒素（LT 或 LT）的 ETEC 菌株。 STa) 腹泻会导致腹泻，理想情况下，有效的 ETEC 疫苗应能预防所有粘附素和两种毒素。但防御 23 种粘附素是不可行的，防御 2 种毒素也非常困难。一直缺乏合适的动物模型来明确评估 ETEC 候选疫苗的功效。在这项研究中，我们将开发一种安全且具有广泛保护性的 ETEC 疫苗，我们将应用多表位。融合抗原 (MEFA) 方法创建粘附素 MEFA 诱导针对 7 种关键粘附素的抗体与 80% 的 ETEC 腹泻病例相关（由具有已知粘附素的 ETEC 菌株引起），并融合 LT 类毒素和 STa 类毒素进行安全的类毒素融合，以诱导中和两种毒素的抗体。 MEFA 和类毒素融合体将被组合（共同给药）或进一步融合在一起（作为 CFA-类毒素） MEFA）诱导广泛保护性的抗粘附素和抗毒素抗体，然后我们将使用新型仔猪和兔双重攻击模型，用于评估候选亚单位疫苗对 ETEC 腹泻的功效。我们的初步研究表明 LT-STa 类毒素融合、粘附素 MEFA 和粘附素-类毒素融合诱导中和毒素和 7 种粘附素并保护猪免受 ETEC 腹泻的抗体，以及兔子和猪是 ETEC 疫苗功效评估的理想动物模型。具有广泛保护性的亚单位 ETEC 疫苗将使数百万儿童和旅行者受益。本研究开发的方法可普遍应用于针对多价疫苗的开发其他疾病。