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

加速产肠毒素大肠杆菌疫苗新抗原的转化开发

基本信息

批准号：
10476194
负责人：
Frederick M Kuhlmann
金额：
$ 7.51万
依托单位：
WASHINGTON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-01-01 至 2022-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10476194
关键词：
ABO blood group system Acute Address Advanced Development Affect Affinity Antibody Avidity Antibody Response Antigens Automobile Driving Award Bacterial Adhesins Bacterial Adhesion Bangladesh Binding Biological Assay Blood Cessation of life Child Childhood Clinical Clinical Trials Cohort Studies Complement Cross-Sectional Studies DNA Sequence Data Development Diarrhea Disease Disease Outcome Elements Enteral Escherichia coli Escherichia coli Infections Escherichia coli Vaccines Evaluation Fostering Foundations Future Genes Genetic Heterogeneity Genomic approach Genomics Goals Growth Health Hemagglutination Homing Human Human Subject Research Immune response Immunity Immunoblotting Immunoglobulin-Secreting Cells Impaired cognition Individual Infection Interferometry Intestines K-Series Research Career Programs Knowledge Learning Lectin Malnutrition Measurement Mentors Metadata Methods Military Personnel Modeling Molecular Morbidity - disease rate Mucins Mucosal Immune Responses Multicenter Studies Mus National Institute of Allergy and Infectious Disease Outcome Pathogenesis Patients Phylogenetic Analysis Play Population Population Heterogeneity Prevention Property Research Resolution Retrospective Studies Risk Role Sampling Serine Protease Severities Specimen Surrogate Markers Testing Toxin Translational Research Vaccine Antigen Vaccine Clinical Trial Vaccine Design Vaccines Validation Virulence adaptive immune response base blood group career career development cohort design diarrheal disease disadvantaged population disorder risk efficacy evaluation enterotoxigenic Escherichia coli experience geographic population gut colonization high risk human data human subject improved international center intestinal epithelium mortality mucinase next generation novel pathogen preclinical evaluation prevent prospective protective efficacy research clinical testing response single molecule real time sequencing sugar tool vaccine candidate vaccine development vaccine efficacy vaccine trial volunteer

项目摘要

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.

项目概要/摘要该提案解决了改进产肠毒素大肠杆菌 (ETEC) 候选疫苗的需要，全世界严重细菌性腹泻的最常见原因之一，该疾病主要影响儿童。世界上最贫穷的地区，导致与腹泻相关的发病率和死亡率过高根据挑战模型中观察到的保护作用，针对 ETEC 的疫苗似乎是可行的。传统的疫苗方法无法推定产生对自然感染的免疫力。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 ETEC 发病机制，补充传统方法本研究的主要目的是促进新抗原的开发，作为有效 ETEC 疫苗的关键贡献者我继续职业发展的两种新抗原是 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 与肠上皮细胞上的 A 型血糖结合。为了推进我的转化研究事业并追求人类学科研究的额外经验，我将推进这些新型抗原的临床前评估，以确定它们在疫苗设计和我们将在未来的临床试验中评估新型ETEC的后续疗效。通过高级测序和基因组学分析等多种手段检测抗原、EtpA 和 EatA 结合功能分析，这些抗原提供的保护可能因血型而异，影响对疫苗功效的解释，疫苗功效将通过回顾性、横断面、为了实现这些目标，我将培养设计、实施和分析数据的能力。我召集了合作者和导师来帮助评估存储的临床数据。标本以及人类受试者新的临床前评估的设计和实施。具体来说，我们将分析对 EtpA 和 EatA 的免疫反应，回答以下问题：  EtpA 和 EatA 在 ETEC 致病变异谱系中的保护是否证明其合理性是否包含在 ETEC 疫苗中？  血型如何改变疾病结果和对 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？  免疫反应的各个方面是否与防止感染相关？如果是，它们可以吗？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同时将使用多种方法来评估每种抗原对疾病的影响这些研究的高潮将提供结果和基于这些抗原的免疫反应。数据推动新型 ETEC 疫苗的合理设计以及评估其功效的快速方法。

项目成果

期刊论文数量（5）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Acute Bacterial Gastroenteritis.

DOI：
10.1016/j.gtc.2021.02.002
发表时间：
2021-06
期刊：
Gastroenterology clinics of North America
影响因子：
3.7
作者：
Fleckenstein JM;Matthew Kuhlmann F;Sheikh A
通讯作者：
Sheikh A

Seroprevalence Study of Conserved Enterotoxigenic Escherichia coli Antigens in Globally Diverse Populations.

DOI：
10.3390/microorganisms11092221
发表时间：
2023-08-31
期刊：
Microorganisms
影响因子：
4.5
作者：
Kuhlmann FM;Grigura V;Vickers TJ;Prouty MG;Iannotti LL;Dulience SJL;Fleckenstein JM
通讯作者：
Fleckenstein JM