A broadly protective vaccine for enterotoxigenic Escherichia coli (ETEC)

针对产肠毒素大肠杆菌 (ETEC) 的广泛保护性疫苗

• 批准号: 8700783
• 负责人: DAVID A SACK
• 金额: $ 34.48万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-08-01 至 2015-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8700783
• 关键词: Acute; Adherence; Adhesions; Adjuvant; Adult; Age; Animal Model; Antibodies; Antigens; Antitoxins; Bacteria; Bacterial Adhesins; Binding; Cessation of life; Child; Chimeric Proteins; Cognitive; Developing Countries; Development; Diarrhea; Disease; Enterotoxins; Epithelial Cells; Epitopes; Escherichia coli; Escherichia coli Adhesins; Escherichia coli Infections; Escherichia coli Vaccines; Family suidae; Fusion Toxin; Goals; Health; Health Benefit; Heating; Heterogeneity; Homeostasis; Immunity; Infant; Infection; Intestines; Laboratories; Lead; Liquid substance; Mediating; Military Personnel; Modeling; Morbidity - disease rate; Mucosal Immune Responses; Mucosal Immunity; Oryctolagus cuniculus; Outcome; Pathogenesis; Peptides; Pilum; Pneumonia; Proteins; Public Health; Research; Rotavirus; Rotavirus Vaccines; Serotyping; Small Intestines; Societies; South Dakota; Structure; Time; Toxin; Toxoids; Universities; Vaccines; Vibrio; Virulence; colonization factor antigens; cross immunity; enterotoxigenic Escherichia coli; experience; holotoxins; immunogenicity; improved; killings; mortality; mutant; novel strategies; nutrition; oral vaccine; pathogen; protective efficacy; receptor; vaccine candidate

DESCRIPTION (provided by applicant): Development of a broadly effective vaccine against diarrhea caused by enterotoxigenic Escherichia coli (ETEC) Project Summary: In this collaborative project between Johns Hopkins and South Dakota State University, we propose developing a broadly effective vaccine to protect against the most common bacterial cause of acute watery diarrhea in the world, enterotoxigenic Escherichia coli (ETEC). In developing countries ETEC cause 280 - 400 million diarrhea cases in children < 5 years, 100 million cases in children over 5 years, and 400 million cases in adults, including travelers and deployed military personnel. Among children, ETEC kill about 300,000 of the 1.3 million diarrhea deaths annually. These infections in children lead to stunting and poor cognitive development placing a burden on society as well as the child. ETEC actually represent a group of Escherichia coli of different serotypes that produce one or both enterotoxins known as heat- labile and heat-stable enterotoxin (LT and STa respectively). They are aided in their pathogenesis by adhesins [also called colonization factor antigens (CFAs)] consisting of specialized pili which facilitate bacteril colonization the small intestine. CFAs, including CFA/I, CFA/II (CS1, CS2, CS3) and CFA/VI (CS4, CS5, CS6) are produced by ETEC strains causing the vast majority of severe ETEC diarrheal episodes. Our vaccine targets these two toxins and the 7 most common adhesins, and is unique in several respects. It delivers these antigens in a single strain, it includes non-toxic antigens to STa, and to the active as well as the binding subunit of the LT toxin, it will hae improved immunogenicity due to the adjuvant activity of the mutant LT as well as its direct binding to the host small intestinal receptor GM1 through the LT binding subunit. We will develop this new ETEC vaccine by creating fusion proteins which incorporate the key adhesins with the ST and LT toxins. We hypothesize that a chimeric CFA antigen carrying representative epitopes from CFA/I, CS1-CS6 adhesin induces anti-adhesin immunity cross protecting against adherence from each adhesin, that a fusion of this multiepitope CFA antigen with a STa13-LT192A2:B toxoid fusion induces broad anti-adhesin immunity and antitoxin immunity against both toxins, and that this adhesin-toxoid fusion can be expressed at a native LT-like holotoxin-structure leading a strong local mucosal immune response. Our unique expertise with pig and rabbit models allows us to unambiguously validate the immunogenicity and efficacy of the new candidate vaccine. Results from this study will lead toward development of an affordable vaccine for ETEC diarrhea with potential to save thousands of children each year -- with a public health impact comparable to rotavirus vaccine.

项目概述：在约翰霍普金斯大学和南达科他州立大学之间的这个合作项目中，我们建议开发一种广泛有效的疫苗，以防止世界上最常见的急性水样腹泻的细菌原因，肠毒素大肠杆菌（ETEC）。在发展中国家，ETEC导致2.8亿至4亿5岁以下儿童腹泻病例，1亿5岁以上儿童腹泻病例，4亿成人腹泻病例，包括旅行者和部署的军事人员。在儿童中，每年因腹泻死亡的130万人中，约有30万人死于ETEC。这些儿童感染导致发育迟缓和认知发育不良，给社会和儿童造成负担。ETEC实际上代表了一组不同血清型的大肠杆菌，它们产生一种或两种肠毒素，即热不稳定肠毒素和热稳定肠毒素（分别为LT和STa）。粘连素（也称为定植因子抗原（CFAs））在其发病机制中起辅助作用，粘连素由促进细菌在小肠定植的特化菌毛组成。CFA，包括CFA/I， CFA/II （CS1, CS2, CS3）和CFA/VI （CS4, CS5, CS6）是由ETEC菌株产生的，导致绝大多数严重的ETEC腹泻发作。我们的疫苗针对这两种毒素和7种最常见的黏附素，在几个方面都是独一无二的。它在单一菌株中递送这些抗原，它包括对STa和LT毒素的活性和结合亚基的无毒抗原，由于突变LT的佐剂活性以及它通过LT结合亚基直接与宿主小肠受体GM1结合，它将具有改善的免疫原性。我们将通过制造融合蛋白来开发这种新的ETEC疫苗，融合蛋白将关键的粘附素与ST和LT毒素结合在一起。我们假设嵌合CFA抗原携带CFA/I、CS1-CS6粘附素的代表性表位诱导抗粘附素免疫，交叉保护每一种粘附素的粘附，这种多表位CFA抗原与STa13-LT192A2:B类毒素融合诱导广泛的抗粘附素免疫和针对两种毒素的抗毒素免疫，并且这种粘附素-类毒素融合可以在天然的t样全毒素结构中表达，导致强烈的局部粘膜免疫反应。我们对猪和兔模型的独特专业知识使我们能够明确地验证新的候选疫苗的免疫原性和有效性。这项研究的结果将有助于开发一种可负担得起的ETEC腹泻疫苗，每年有可能拯救数千名儿童，其公共卫生影响可与轮状病毒疫苗相媲美。