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

基于纳米技术的平台，用于开发针对阿片类药物使用障碍（OUD）的下一代疫苗

• 批准号: 10751208
• 负责人: Fatima Alamin Awad Alkareem Hamid
• 金额: $ 3.5万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-01 至 2026-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10751208
• 关键词: Acceleration; Active Immunization; Address; Adjuvant; Affect; Affinity; Agonist; Antibodies; Antibody Response; Antibody titer measurement; Antigen-Presenting Cells; Antigens; B Cell Proliferation; B cell differentiation; B-Cell Activation; B-Lymphocytes; Biodistribution; Biological Availability; Bradycardia; Brain; CD4 Positive T Lymphocytes; COVID-19 vaccine; Cell Cycle Kinetics; Cells; Clinical; Clinical Trials; Communication; Communities; Complex; Conjugate Vaccines; Data; Dendritic Cells; Development; Drug Targeting; Economic Burden; Ensure; Epidemic; FDA approved; Fellowship; Fentanyl; Flow Cytometry; Formulation; Funding; Future; Glycolates; Haptens; Helper-Inducer T-Lymphocyte; Hybrids; Immunoglobulin G; Immunoglobulins; Immunohistochemistry; Immunology; Immunomodulators; In Vitro; Individual; Injections; Innate Immune Response; Kinetics; Lipid A; Lipids; Liposomes; Macrophage; Measures; Memory; Memory B-Lymphocyte; Mentors; Mentorship; Methods; Modeling; Molecular; Monitor; Motor Activity; Mus; Nanotechnology; National Institute of Drug Abuse; Natural Immunity; Nature; Nicotine; Opioid; Opioid agonist; Overdose; Oxycodone; Patients; Pharmaceutical Preparations; Pharmacology; Pharmacotherapy; Phase I Clinical Trials; Plasma; Plasma Cells; Polymers; Positioning Attribute; Pre-Clinical Model; Preclinical Testing; Process; Public Health; Quantitative Reverse Transcriptase PCR; Research; Rewards; Safety; Scientist; Self Administration; Serum; Site; Spleen; Structure of germinal center of lymph node; Substance Use Disorder; Substance abuse problem; TLR4 gene; TLR7 gene; Testing; Time; Training; Translational Research; Translations; Vaccinated; Vaccination; Vaccine Design; Vaccines; Ventilatory Depression; abuse liability; adaptive immune response; adaptive immunity; addiction; antagonist; antinociception; career; design; draining lymph node; fluorescence imaging; immune activation; immunogenicity; improved; in vivo; in vivo evaluation; in vivo imaging; individual variation; lipid nanoparticle; lymph nodes; migration; multidisciplinary; nanocarrier; nanoformulation; nanoparticle; nanovaccine; next generation; nicotine vaccine; novel; novel strategies; novel vaccines; opioid use; opioid use disorder; overdose death; pharmacologic; poly(lactic acid); polyclonal antibody; prevent; prophylactic; public health emergency; rational design; recruit; resiquimod; response; secondary lymphoid organ; side effect; skills; success; targeted delivery; therapeutically effective; time use; trafficking; vaccine candidate; vaccine delivery; vaccine development; vaccine efficacy; vaccine evaluation; vaccine formulation; vaccine platform; vaccinology

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.

项目摘要： 高度复杂的 OUD 和用药过量流行病造成了巨大的公共卫生和经济负担。当前的 FDA 批准的针对 OUD 和过量的药物疗法使用阿片受体激动剂和拮抗剂。 这些疗法由于其副作用、患者可及性不佳和治疗效果总体有限。 合规性以及滥用和转移的责任。疫苗提供了一种新的治疗选择，既可以替代 并补充现有措施。临床前测试表明，抗阿片类药物疫苗是一种高度有效的疫苗。 选择性长期治疗和预防策略，防止阿片类药物引起的镇痛， 临床前模型中的运动活动、呼吸抑制、心动过缓和自我给药。以前的 成瘾疫苗的临床试验证明了对获得最高抗体的受试者的有效性 (Ab) 滴度，强调需要设计更有效的疫苗并了解变异的基础 个人功效。因此，该提案的重点是开发下一代基于纳米颗粒的抗阿片类药物 疫苗并破译其功效背后的分子和细胞机制。我们的团队开发了一个 新型脂质聚合物混合纳米粒子（LPNP）平台，增强了结合疫苗的功效 对抗尼古丁和羟考酮。基于这些初步数据，我们建议进一步剖析分子 在此基础上提高功效并测试纳米疫苗的成分和佐剂显示如何确定 先天性和适应性免疫激活以及特定的细胞和分子机制是否是疫苗的基础 对 OUD 的功效。 AIM1将测试不同聚合物和佐剂展示方法对功效的影响 抗羟考酮纳米疫苗。以及结合疫苗的纳米制剂如何影响递送和 疫苗成分的生物利用度。研究将调查疫苗在小鼠中的功效、IgG 抗体滴度和 Ig 脾脏和淋巴内生物分布、积累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性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态响应 疫苗接种，解决有助于功效的关键细胞亚群，并评估 B 细胞的大小 回应。研究结果将提供一种可以轻松适应其他滥用物质的模型疫苗。这样的 这些信息将指导未来的疫苗设计以及合理选择最合适的配方。 给定的抗原。拟议的指导研究和 F31 奖学金是非常宝贵的培训和 我努力成为一名独立科学家的专业发展机会。这种假设驱动的 多学科项目包含各种最先进的方法，这是在以下方面取得优异成绩的先决条件 免疫学、药理学和药物滥用交叉领域的转化研究。的指导 NIDA 资助的专家将确保拟议研究的成功完成和有效的 向科学界传达研究成果。