Evaluation of Memory Responses and Biomarkers from a Phase 1 Enterotoxigenic Escherichia coli (ETEC) Intramuscular Subunit Vaccine with dmLT Adjuvant

使用 dmLT 佐剂的 1 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: 10387442
• 负责人: Elizabeth B Norton
• 金额: $ 68.6万
• 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: 2021-05-24 至 2023-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10387442
• 关键词: Adjuvant; Adverse event; Antibodies; Antigen-Presenting Cells; Antigens; Area; Avidity; B-Lymphocytes; Bacterial Adhesins; Biological; Biological Assay; Biological Markers; CREB1 gene; Calcium; Campylobacter; Cells; Cellular Immunity; Chemicals; Child; Clinical Trials; Complement; Cyclic AMP; Cyclic AMP-Dependent Protein Kinases; Development; Diarrhea; Dose; Ensure; Escherichia coli Infections; Escherichia coli Vaccines; Evaluation; Event; Exposure to; Formulation; Freezing; Future; Genetic Transcription; Goals; Homing; Human; Immune; Immune response; Immunity; Immunization; Immunoglobulin-Secreting Cells; Immunologics; In Vitro; Infection; Intramuscular; Intramuscular Injections; Knockout Mice; Longevity; Measures; Memory; Metabolic; Metabolic Pathway; Metabolism; Military Personnel; Modeling; Molecular; Mucosal Immunity; Mus; Oral; Oxidative Phosphorylation; Peripheral Blood Mononuclear Cell; Phase; Phase I Clinical Trials; Pilot Projects; Public Health; Publications; Reporting; Risk; Route; Safety; Sampling; Serious Adverse Event; Serum; Serum Proteins; Shapes; Shigella; Signal Pathway; Signal Transduction; Skin; Stains; Subunit Vaccines; T memory cell; Testing; Time; Toxin; Toxoids; Transcriptional Activation; Vaccination; Vaccine Antigen; Vaccine Clinical Trial; Vaccines; base; biomarker identification; clinical trial analysis; cohort; colonization factor antigens; combinatorial; cytokine; design; diarrheal disease; enterotoxigenic Escherichia coli; first-in-human; immunogenicity; in vivo; inhibitor/antagonist; insight; lipid metabolism; metabolomics; mouse model; nonhuman primate; phase I trial; potential biomarker; protein metabolite; response; response biomarker; transcription factor; vaccination outcome; vaccine development; vaccine efficacy; vaccine trial

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 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 complete 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 initiated by CssBA+dmLT stimulation in immune cells can serve as biomarkers of immunity; and (4) what are the key molecular mechanisms of the immunization formulation that 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. In addition, we will validate findings with cellular analyses, mouse models, and samples from a related ETEC Phase 2b vaccine trial. 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、旅行者和儿童细菌感染性腹泻的主要原因。 在危险地区部署军事人员。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一期疫苗试验（NCT03404674）。 CS6 亚基抗原 CssBA 与 LT-R192G/L211A 联合肌内剂量递增 （dmlT）。没有报告严重的不良事件，我们在几个队列中观察到很强的免疫原性， 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。 该提案的目标是完成对来自 ETEC 第一阶段的血清和 PBMC 样本的分析 临床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 我们提出的研究旨在探索（1）疫苗接种剂量如何调节记忆力和寿命的发展 体液反应的多样性； (2) 疫苗接种如何改变持久细胞免疫的发展； (3)CssBA+dmLT刺激免疫细胞引发的早期信号事件是否可以作为 免疫生物标志物； (4) 免疫制剂的关键分子机制是什么？ 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， 包括转录和代谢组学测定。此外，我们将通过细胞分析验证研究结果， 小鼠模型，以及相关 ETEC 2b 期疫苗试验的样本。这些发现将有助于 通过肠胃外途径开发人用 ETEC 疫苗，并提供机制见解 指导疫苗接种结果的关键事件。