Nanotechnology-based platform for the development of next-generation vaccines against opioid use disorder (OUD)

项目摘要： 高度复杂的OUD和过量流行给公共卫生和经济带来了巨大的负担。当前 FDA批准的针对OUD和过量的药物治疗使用阿片受体激动剂和拮抗剂。 这些疗法总体上显示出有限的疗效，原因是它们的副作用、次佳的患者准入和 合规，以及滥用和转移的责任。疫苗提供了一种新的治疗选择，既是另一种选择 并且是对现有措施的补充。临床前试验表明，抗阿片类药物疫苗是一种高度有效的 选择性长期治疗和预防策略，防止阿片类药物诱导的抗伤害反应， 临床前模型中的运动活动、呼吸抑制、心动过缓和自我给药。上一首 成瘾疫苗的临床试验证明，抗体水平最高的受试者有效。 (AB)效价，强调需要设计更有效的疫苗，并了解疫苗变异性的基础 个体效能。因此，本提案重点发展基于纳米颗粒的下一代抗阿片类药物 疫苗和破译其功效背后的分子和细胞机制。我们的团队开发了一种 新型脂质聚合物杂化纳米粒(LpNP)平台，增强结合疫苗的效力 对抗尼古丁和羟考酮。在这些初步数据的基础上，我们建议进一步解剖分子 在此基础上增加了效力，并测试了纳米疫苗的组成，以及佐剂的显示情况 先天和获得性免疫激活以及疫苗背后是否存在特定的细胞和分子机制 对乌德的药效。AIM1将测试不同聚合物和佐剂展示方法对疗效的影响 针对羟考酮的纳米疫苗。以及结合疫苗的纳米制剂如何影响传递和 疫苗成分的生物利用度。研究将调查疫苗在小鼠中的效力、免疫球蛋白抗体效价和免疫球蛋白 脾和淋巴中生物分布、蓄积和定位的亚类和疫苗动力学 节点。AIM2将阐明不同的纳米疫苗配方是否在先天和适应性方面表现出差异 免疫反应。研究将剖析先天免疫的体外激活和体内动力学响应 接种疫苗，解决有助于疗效的关键细胞亚群，以及评估B细胞的大小 回应。结果将提供一种模型疫苗，可以很容易地适应其他滥用物质。是这样的 信息将指导未来的疫苗设计和合理选择最合适的疫苗配方 给出了抗原。建议的辅导性学习和F31奖学金是非常宝贵的培训和 随着我努力成为一名独立的科学家，我也有了职业发展的机会。这一假设驱动了 多学科项目包含各种最先进的方法，这些方法是出类拔萃的先决条件 免疫学、药理学和药物滥用之间的转译研究。的指导作用 NIDA资助的专家将确保成功完成拟议的研究并有效地 向科学界传达研究成果。

Project Abstract: The highly complex OUD and overdose epidemic poses a huge public health and economic burden. Current FDA-approved pharmacotherapies against OUD and overdose use opioid receptor agonists and antagonists. These therapies show overall limited efficacy, due to their side effects, suboptimal patient access and compliance, and liability for abuse and diversion. Vaccines offer a new treatment option that is both alternative and complementary to existing measures. Preclinical testing demonstrated anti-opioids vaccines as a highly selective long-lasting treatment and prophylactic strategy that protects against opioid-induced antinociception, motor activity, respiratory depression, bradycardia, and self-administration in pre-clinical models. Previous clinical trials of addiction vaccines showed proof of efficacy in those subjects who achieved the highest antibody (Ab) titers, highlighting the need to design more effective vaccines and understanding the basis for variability in individual efficacy. Hence, this proposal focuses on developing next-generation nanoparticle-based anti-opioid vaccines and deciphering molecular and cellular mechanisms underlying their efficacy. Our team developed a novel lipid polymer hybrid nanoparticles (LPNP) platform, that enhanced the efficacy of conjugate vaccines against nicotine and oxycodone. Based on these preliminary data, we propose further dissecting the molecular basis of this increased efficacy and testing how nanovaccines composition, and adjuvant display determine innate and adaptive immune activation and whether specific cellular and molecular mechanisms underlie vaccine efficacy against OUD. AIM1 will test the effect of different polymers and adjuvant display methods on efficacy of nanovaccine against oxycodone. As well as how nanoformulation of conjugate vaccine affect the delivery and bioavailability of vaccine components. Studies will investigate vaccine efficacy in mice, IgG antibody titer and Ig subclass and vaccine kinetics in terms of biodistribution, accumulation and localization within spleen and lymph nodes. AIM2 will elucidate whether different nanovaccine formulations show distinctions in innate and adaptive immune responses. Studies will dissect innate immunity in vitro activation and in vivo dynamics in response to vaccination, addressing key cell subsets contributing to efficacy, as well as assess the magnitude of B cell responses. Results will provide a model vaccine that can be easily adapted to other abused substances. Such information will guide future vaccine design and the rational selection of the most appropriate formulation for a given antigen. The proposed mentored studies and this F31 fellowship are invaluable training and professional development opportunity as I strive to become an independent scientist. This hypothesis-driven multidisciplinary project encompasses various state-of-art approaches that are prerequisites to excel in translational research at the interface of immunology, pharmacology and substance abuse. The mentorship of NIDA-funded experts will ensure the successful completion of the proposed studies and the effective communication of research findings to the scientific community.