A broadly protective vaccine for enterotoxigenic Escherichia coli (ETEC)

描述(由申请人提供)：开发一种广谱有效的疫苗来对抗产肠毒素大肠杆菌(ETEC)引起的腹泻(ETEC)项目摘要：在约翰霍普金斯大学和南达科他州立大学的这个合作项目中，我们建议开发一种广效疫苗来预防世界上最常见的导致急性水样腹泻的细菌-产肠毒素大肠杆菌(ETEC)。在发展中国家，ETEC导致2.8亿至4亿例儿童和5岁以下儿童腹泻病例，1亿例5岁以上儿童腹泻病例，4亿例成人病例，包括旅行者和部署的军事人员。在儿童中，ETEC每年导致130万腹泻死亡中的约30万人死亡。这些对儿童的感染导致发育迟缓和认知发育不良，给社会和儿童带来负担。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，称为热不稳定肠毒素和热稳定肠毒素(分别为LT和STA)。粘附素[也称为定植因子抗原(CFAs)]由特殊的菌毛组成，促进细菌在小肠的定植，有助于它们的发病。包括CFA/I、CFA/II(CS1、CS2、CS3)和CFA/VI(CS4、CS5、CS6)在内的CFA是由ETEC菌株产生的，导致绝大多数ETEC严重腹泻发作。我们的疫苗针对这两种毒素和7种最常见的粘附素，在几个方面是独一无二的。它以单一的菌株递送这些抗原，它包括无毒的抗原到stA，它包括LT毒素的活性亚基和结合亚基，由于突变体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，它将具有更好的免疫原性。我们将通过创建融合蛋白来开发这种新的ETEC疫苗，该融合蛋白将关键粘附素与ST和LT毒素结合在一起。我们假设，携带CFA/I、CS1-CS6粘附素代表性表位的嵌合CFA抗原诱导抗粘附素免疫交叉保护每个粘附素的粘连，该多表位CFA抗原与STa13-LT192A2：B类毒素融合可诱导广泛的抗粘附素免疫和针对这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LT样全毒素结构上表达，从而导致强烈的局部粘膜免疫反应。我们在猪和兔模型方面的独特专业知识使我们能够毫不含糊地验证新候选疫苗的免疫原性和有效性。这项研究的结果将导致开发一种负担得起的ETEC腹泻疫苗，每年有可能拯救数千名儿童--对公共健康的影响可与轮状病毒疫苗相媲美。

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.