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Identifying mechanisms and biomarkers predictive of individual variability in efficacy of vaccines against opioid use disorder

识别预测阿片类药物使用障碍疫苗功效个体差异的机制和生物标志物

基本信息

批准号：
10313872
负责人：
Bethany K Crouse
金额：
$ 2.7万
依托单位：
UNIVERSITY OF MINNESOTA
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：
2021-11-01 至 2022-08-19
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10313872
关键词：
Identifying mechanisms biomarkers predictive individual

项目摘要

Project Summary. In the United States, there are over 2.5 million people diagnosed with opioid use disorder (OUD) and over 47,000 opioid-related fatal overdoses occur annually. Current FDA-approved medications against OUD and overdose consist of opioid receptor agonists and antagonists, which overall show limited efficacy, adverse effects, suboptimal patient access and compliance, abuse liability, and illicit diversion. As an alternative or complimentary strategy to small molecule-based pharmacotherapies, vaccines offer a safe and long-lasting therapeutic or prophylactic strategy to counteract OUD and fatal overdoses. Anti-opioid vaccines have shown proof of efficacy and selectivity in reducing opioid-induced antinociception, respiratory depression, bradycardia, opioid intravenous self-administration, and lethality in animal models. Despite promising pre-clinical data, vaccine clinical efficacy may still be limited to a subset of immunized individuals that achieve optimal antibody responses against the target opioid. Hence, the focus of this proposal is to accelerate translation of anti-opioid vaccines by identifying mechanisms and biomarkers correlated with optimal vaccine-induced protection against opioids. Our group has previously found that blockade of the cytokine interleukin-4 (IL-4) increased vaccine efficacy against oxycodone in mice, supporting the hypothesis that changes in IL-4 signaling modulate or predict vaccine efficacy against opioids. AIM1 tests whether IL-4 modulation underlies cellular and molecular processes involved in activation of B cell lymphocytes and generation of optimal antibody responses against opioids. AIM1 will test affinity maturation, isotype switching, antibody secretion kinetics, and transcriptomic changes in opioid-specific B cells. AIM2 tests whether IL-4 or its downstream signaling components (e.g., IL-4 receptor, STAT6) are predictive biomarkers of vaccine efficacy in both mice and human patients immunized with an oxycodone conjugate vaccine currently in Phase I clinical trials (NCT04458545). Results from these studies will provide a blueprint to develop more effective next-generation vaccine formulations and to identify putative biomarkers predictive of vaccine efficacy against opioids. Such information will accelerate pre-clinical vaccine development and support patient stratification in clinical trials and clinical implementation. Training. Completing the experiments outlined in this proposal will support my training and career goals to become an independent scientist. This hypothesis-driven project proposes multidisciplinary experiments allowing me to develop a broad range of technical skills to study a clinically relevant problem in-depth. I will also be mentored by leaders and experts in the fields of vaccinology, opioid use disorders, and immunology. Additionally, I will have the unique opportunity to gain expertise in translational science and human immunology through an ongoing clinical trial of a novel anti-opioid vaccines. This will provide the necessary skills to advance my career focusing on using innovative immunological principles to develop treatments for substance use disorder and related comorbid diseases.

项目摘要。在美国，有超过250万人被诊断患有阿片类药物使用障碍（OUD），每年都发生与类阿片有关的致命过量。目前FDA批准的治疗OUD和过量的药物包括阿片受体激动剂和拮抗剂，它们总体上显示出有限的功效，副作用，次优的患者获取和依从性、滥用责任和非法转移。作为替代或补充作为小分子药物疗法的战略，疫苗提供了一种安全和持久的治疗或预防性策略，以对抗OUD和致命的过量。抗阿片类药物疫苗已显示出有效性以及选择性减少阿片类药物诱导的抗伤害感受、呼吸抑制、心动过缓、阿片类药物静脉内自我给药和动物模型中的致死性。尽管有很好的临床前数据，临床效力可能仍然限于获得最佳抗体应答的免疫个体的子集针对目标阿片类药物。因此，该提案的重点是加速抗阿片类药物疫苗的转化通过识别与最佳疫苗诱导的阿片类药物保护相关的机制和生物标志物。我们的研究小组以前发现，阻断细胞因子白细胞介素-4（IL-4）可以提高疫苗的效力支持IL-4信号传导的变化调节或预测疫苗的假设对阿片类药物的疗效。AIM 1测试IL-4调节是否是所涉及的细胞和分子过程的基础在活化B细胞淋巴细胞和产生针对阿片样物质的最佳抗体应答中。AIM1将测试亲和力成熟、同种型转换、抗体分泌动力学和阿片样物质特异性表达的转录组学变化。 B细胞。AIM 2测试IL-4或其下游信号传导组分（例如，IL-4受体，STAT6）是用羟考酮免疫的小鼠和人类患者中疫苗效力的预测生物标志物目前处于I期临床试验的偶联疫苗（NCT 04458545）。这些研究的结果将提供开发更有效的下一代疫苗制剂和确定推定生物标志物的蓝图预测疫苗对阿片类药物的有效性。这些信息将加速临床前疫苗的开发并支持临床试验和临床实施中的患者分层。训练完成本建议书中概述的实验将支持我的培训和职业目标，成为独立的科学家。这个假设驱动的项目提出了多学科实验这使我能够发展广泛的技术技能，以深入研究临床相关问题。我也会由疫苗学，阿片类药物使用障碍和免疫学领域的领导者和专家指导。此外，我将有独特的机会获得转化科学和人类免疫学方面的专业知识通过一项正在进行的新型抗阿片类药物疫苗的临床试验。这将提供必要的技能，我的职业生涯专注于使用创新的免疫学原理来开发药物使用的治疗方法疾病和相关的共病。