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

项目总结/摘要 该提案解决了改进产肠毒素大肠杆菌（ETEC）候选疫苗的需求， 这是全世界严重细菌性腹泻最常见的原因之一。这种疾病主要影响儿童， 世界上最贫穷的地区，导致与疟疾有关的发病率和死亡率过高 病基于攻毒模型中观察到的保护作用，靶向ETEC的疫苗似乎是可行的， 对自然感染的免疫力的假定发展。传统的疫苗方法无法 适应ETEC病原体的广泛多样性，导致我的导师发现新抗原， 参与ETEC发病机制，这补充了传统的方法。本研究的主要目的是 推进新型抗原的开发，作为有效ETEC疫苗的关键贡献者， 我的职业发展。这两种新的抗原是EatA，一种降解肠粘蛋白的粘蛋白酶 允许病原体进入宿主和EtpA，EtpA与肠上皮细胞上的血型A糖结合。 为了推进我的转化研究事业，并在人类受试者研究方面积累更多经验，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中的效用， 在未来的临床试验中进行后续疗效评价。我们将评估新的ETEC的保护 抗原，EtpA和EatA通过各种手段，包括先进的测序和基因组学分析 结合功能分析。这些抗原提供的保护可能因血型而异， 影响疫苗有效性的解释，将通过回顾性，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。我召集了合作者和导师，以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价。 具体来说，我们将分析对EtpA和EatA的免疫应答，回答以下问题： EtpA和EatA在ETEC致病变种谱中的保守性是否证明了其 是否包含ETEC疫苗？ 血型如何改变疾病结果和对EtpA+ ETEC感染的免疫反应？ 血型对疫苗临床试验的设计和评估有什么影响？ 评估EatA和EtpA免疫应答的最佳方法是什么？ 免疫反应的各个方面是否与保护免受感染相关，如果是， 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 虽然将使用多种方法来评估这些抗原中的每一种对疾病的影响 结果和基于这些抗原的免疫反应。这些研究的结果将提供 数据驱动新型ETEC疫苗的合理设计以及快速评估其有效性的方法。

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.