Accelerating Translational Development of Novel Antigens for an Enterotoxigenic E. coli Vaccine

项目摘要/摘要 这项提案涉及改进产肠毒素大肠杆菌(ETEC)候选疫苗的需要， 这是全球严重细菌性腹泻最常见的原因之一。这种疾病主要折磨着#年的儿童。 世界上最贫穷的地区，导致与腹泻相关的过度发病率和死亡率 生病了。根据在挑战模型中观察到的保护作用和针对ETEC的疫苗似乎是可行的 对自然感染的免疫力的假定发展。传统的疫苗方法已经无法 适应ETEC病原体的广泛多样性，导致我的导师发现了新的抗原， 参与了ETEC的发病机制，是对传统方法的补充。这项研究的主要目的是 促进新抗原的开发，使其成为有效的ETEC疫苗的关键因素 我的持续职业发展。这两种新的抗原是eata，一种降解肠道粘蛋白的粘蛋白酶。 允许病原体进入宿主和EtpA，EtpA与肠道上皮细胞上的A型血糖类结合。 为了推进我的翻译研究事业，并在人类学科研究方面寻求更多经验，我 将推进这些新抗原的临床前评估，以确定它们在疫苗设计和 在未来的临床试验中进行后续疗效评估。我们将评估新型ETEC的保护 通过包括高级测序和基因组分析在内的各种手段获得抗原、etpA和eATA 结合功能分析。这些抗原提供的保护可能因血型不同而不同， 影响对疫苗效力的解释，将通过回顾、横断面、 和队列研究。为了实现这些目标，我将培养设计、实施和分析数据的能力 从人体试验中。我已经召集了合作者和导师来帮助评估存储的临床 以及在人类受试者中设计和实施新的临床前评估。 具体地说，我们将分析EtpA和EATA的免疫反应，回答以下问题： 是否证明etpA和eATA在ETEC通路中的保守性是合理的 是否包含在ETEC疫苗中？ 血型如何改变疾病结局和对EtpA+ETEC感染的免疫反应？ 血型对临床疫苗试验的设计和评估有什么影响？ 评估EATA和EtpA免疫反应的最佳方法是什么？ 是免疫反应的几个方面，与防止感染相关，如果是这样的话，它们是否 提高未来ETEC疫苗研究的效率？ 基因组学方法以及经典的分子研究将评估这些抗原的保守性。 虽然将使用各种方法来评估每一种抗原对疾病的影响 结果和基于这些抗原的免疫反应。这些研究的结果将提供 驱动新型ETEC疫苗合理设计的数据以及评估其有效性的快速手段。

Project Summary/Abstract This proposal addresses the need to improve candidate vaccines for enterotoxigenic Escherichia coli (ETEC), one of the commonest causes of severe bacterial diarrhea worldwide. The disease primarily afflicts children in the poorest regions of the world, contributing to excessive morbidity and mortality associated with diarrheal illness. Vaccines targeting ETEC appear feasible based on protection observed in challenge models and the presumptive development of immunity to natural infection. Traditional vaccine approaches have been unable accommodate the extensive diversity of ETEC pathogens leading to my mentors discovery of novel antigens, involved in ETEC pathogenesis, that compliment traditional approaches. The main objective of this study is to advance the development of novel antigens as key contributors to an effective ETEC vaccine dovetailing with my continued career development. The two novel antigens are EatA, a mucinase degrading intestinal mucins allowing pathogen access to the host and EtpA, which binds to blood group A sugars on the intestinal epithelia. To advance my translational research career and pursue additional experience in human subjects research, I will advance the pre-clinical evaluation of these novel antigens to determine their utility in vaccine design and subsequent efficacy evaluation in future clinical trials. We will assess the conservation of novel ETEC antigens, EtpA and EatA through a variety of means including advanced sequencing and genomics analysis combined with functional analysis. The protection afforded by these antigens may differ based on blood type, impacting the interpretation of vaccine efficacy which will be assessed through retrospective, cross-sectional, and cohort studies. To achieve these aims, I will cultivate an ability to design, implement, and analyze data from human trials. I have assembled collaborators and mentors to aid in the evaluation of stored clinical specimens as well as the design and implementation of new pre-clinical evaluations in human subjects. Specifically, we will analyze the immune responses to EtpA and EatA answering the following questions:  Does the conservation of EtpA and EatA across the spectrum of the ETEC pathovar justify their inclusion in ETEC vaccines?  How does blood type alter disease outcomes and immune responses to EtpA+ ETEC infections?  What impact does blood type have on the design and evaluation of clinical vaccine trials?  What is the best means to evaluate EatA and EtpA immune responses?  Are aspects of the immune response correlated with protection from infection and if so, can they improve the efficiency of future ETEC vaccine studies? Genomics approaches as well as classic molecular studies will assess the conservation of these antigens while a variety of methods will be used to assess the consequences of each of these antigens on disease outcomes and the immune response based on these antigens. The culmination of these studies will provide data driving the rational design of novel ETEC vaccines as well as the rapid means to assess their efficacy.