Evaluation of Memory Responses and Biomarkers from a Phase IEnterotoxigenic Escherichia coli (ETEC) Intramuscular SubunitVaccine with dmLT Adjuvant

使用 dmLT 佐剂的 I 期产肠毒素大肠杆菌 (ETEC) 肌内亚单位疫苗的记忆反应和生物标志物评估

• 批准号: 10357242
• 负责人: Elizabeth B Norton
• 金额: $ 66.96万
• 依托单位: TULANE UNIVERSITY OF LOUISIANA
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-24 至 2026-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10357242
• 关键词: Adjuvant; Antibodies; Antigen-Presenting Cells; Antigens; Area; Automobile Driving; Avidity; B-Lymphocytes; Bacterial Adhesins; Biological Assay; Biological Markers; CREB1 gene; Calcium; Campylobacter coli; Cells; Cellular Immunity; Child; Clinical; Clinical Trials; Combined Vaccines; Cyclic AMP; Dermal; Development; Diarrhea; Dose; Escherichia coli; Escherichia coli Infections; Escherichia coli Vaccines; Evaluation; Event; Formulation; Freezing; Future; Genetic; Genetic Transcription; Goals; Homing; Human; Immune response; Immunity; Immunization; Immunoglobulin-Secreting Cells; Immunologics; In Vitro; Individual; Infection; Intramuscular; Intramuscular Injections; Knockout Mice; Longevity; Measures; Memory; Metabolic; Metabolic Pathway; Metabolism; Military Personnel; Modeling; Molecular; Mucosal Immunity; Oral; Outcome; Oxidative Phosphorylation; Peripheral Blood Mononuclear Cell; Phase; Phase I Clinical Trials; Proteins; Public Health; Reporting; Risk; Role; Route; Safety; Sampling; Serious Adverse Event; Serum; Serum Proteins; Shapes; Signal Transduction; Signaling Protein; Stains; Subunit Vaccines; T memory cell; Testing; Toxin; Toxoids; Vaccination; Vaccine Antigen; Vaccine Clinical Trial; Vaccines; base; clinical trial analysis; cohort; cytokine; design; diarrheal disease; enterotoxigenic Escherichia coli; first-in-human; immune activation; immunogenicity; in vivo; insight; integrin alpha4beta7; lipid metabolism; metabolomics; mouse model; mutant; novel; phase I trial; potential biomarker; protein metabolite; response; response biomarker; transcription factor; vaccination outcome; vaccine development; vaccine efficacy; vaccine trial; vaccine-induced immunity

Enterotoxigenic E. coli (ETEC) is a major cause of bacterial infectious diarrhea in children, travelers and deployed military personnel in risk areas. As such, development of a vaccine would be advantageous for public health. One strategy is to use subunits of colonization factors combined with toxoids of heat-labile toxin (LT). Recently, a first-in-humans safety and immunogenicity Phase 1 vaccine trial (NCT03404674) was conducted. with dose- escalating intramuscular delivery of CS6-subunit antigen CssBA combined with LT-R192G/L211A (dmLT). No serious adverse events were reported and we observed strong humoral immunogenicity in several cohorts, notably related to dmLT dose. Yet a complete analysis of clinical trial samples, including humoral and cellular memory is lacking. As this vaccine trial indicates, dmLT is not only an LT toxoid but also a potent adjuvant that stimulates immunity to co-delivered antigens; however, there is a gap in our understanding of molecular mechanisms responsible for initiating vaccination outcomes with antigens co-delivered with dmLT. The objective of this proposal is to expand analysis on serum and PBMC samples from an ETEC Phase 1 clinical trial and to define the key biomarkers and molecular mechanisms directing vaccine outcomes. In the proposed studies we aim to explore (1) how vaccination doses modulated development of memory, longevity and diversity of the humoral response; (2) how vaccination altered development of durable cellular immunity; (3) whether early signaling events can serve as biomarkers of immunity; and (4) what molecular mechanisms during immunization shape vaccination outcomes. To do so we will analyze our stored clinical trial samples and perform a number of sophisticated analyses, including transcriptional and metabolomics assays using samples from a related ETEC Phase 2b vaccine- efficacy trail to define signatures of vaccine induced protection which we will then validate using the Phase 1 trial samples. In addition, we will validate findings with cellular analyses and mouse models. These findings will help with the development of an ETEC vaccine for human use by parenteral route and also provide mechanistic insight into key events directing vaccination outcomes.

产肠毒素大肠杆菌 (ETEC) 是儿童、旅行者和部署人员细菌感染性腹泻的主要原因 危险地区的军事人员。因此，疫苗的开发将有利于公众健康。 一种策略是使用定植因子亚基与不耐热毒素 (LT) 的类毒素相结合。最近， 进行了首次人体安全性和免疫原性 1 期疫苗试验 (NCT03404674)。与剂量- 逐步肌内递送 CS6 亚基抗原 CssBA 与 LT-R192G/L211A (dmLT) 相结合。不 报告了严重的不良事件，我们在几个队列中观察到强烈的体液免疫原性， 与 dmLT 剂量密切相关。对临床试验样本（包括体液和细胞）的完整分析 内存不足。正如该疫苗试验所示，dmLT 不仅是一种 LT 类毒素，而且还是一种有效的佐剂 刺激对共同传递的抗原的免疫力；然而，我们对分子的理解存在差距 负责启动与 dmLT 共同递送的抗原的疫苗接种结果的机制。 该提案的目的是扩大对来自 ETEC 1 期临床的血清和 PBMC 样本的分析 试验并确定指导疫苗结果的关键生物标志物和分子机制。在提议的 我们旨在探索的研究 (1) 疫苗接种剂量如何调节记忆、寿命和多样性的发展 体液反应； (2) 疫苗接种如何改变持久细胞免疫的发展； (3)是否早 信号事件可以作为免疫的生物标志物； (4) 免疫过程中的分子机制 塑造疫苗接种结果。 为此，我们将分析我们存储的临床试验样本并进行许多复杂的分析， 包括使用来自相关 ETEC 2b 期疫苗的样本进行转录和代谢组学测定 - 功效试验来定义疫苗诱导保护的特征，然后我们将使用第一阶段试验进行验证 样品。此外，我们将通过细胞分析和小鼠模型验证研究结果。这些发现将有助于 随着 ETEC 疫苗的开发，供人类通过肠胃外途径使用，并提供机制 深入了解指导疫苗接种结果的关键事件。