Novel nanovaccines against opioid use disorders

针对阿片类药物使用障碍的新型纳米疫苗

• 批准号: 9796252
• 负责人: Marco Pravetoni
• 金额: $ 153.74万
• 依托单位: VIRGINIA POLYTECHNIC INST AND ST UNIV
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-07-15 至 2021-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9796252
• 关键词: Adjuvant; Adverse effects; Agonist; Analytical Chemistry; Antibodies; Antibody Response; Antigen-Presenting Cells; B-Lymphocytes; Behavior; Behavioral; Benchmarking; Binding; Biological Assay; Brain; CD4 Positive T Lymphocytes; Carrier Proteins; Cells; Charge; Combined Vaccines; Complex; Conjugate Vaccines; Development; Diphtheria Toxin; Dose; Economic Burden; FDA approved; Fentanyl; Formulation; Future; Glycolates; Goals; Haptens; Hybrids; Immune; Immune response; Immunization; Immunoglobulin G; Immunologic Adjuvants; Incidence; Individual; Industry; Intervention; Intravenous; Keyhole Limpet Hemocyanin; Lead; Lipids; Maintenance; Modeling; Molecular; Morphology; Mus; Nicotine; Opioid; Opioid Antagonist; Overdose; Oxycodone; Pain management; Pathway interactions; Patients; Pharmaceutical Preparations; Pharmacology; Pharmacotherapy; Phase; Polymers; Process; Production; Proteins; Rattus; Safety; Self Administration; Series; Serum; Substance Use Disorder; Surface; T-Lymphocyte Epitopes; Testing; Toxic effect; Toxicology; United States; Vaccinated; Vaccination; Vaccines; Ventilatory Depression; adaptive immune response; addiction; base; chemical property; cost effective; cross reacting material 197; cross reactivity; design; dosage; drug distribution; drug induced behavior; efficacy study; efficacy testing; endogenous opioids; experience; immunogenicity; improved; innovation; nano; nanocarrier; nanoformulation; nanoparticle; nanovaccine; novel; novel strategies; novel vaccines; opioid misuse; opioid use; opioid use disorder; particle; physical property; pre-clinical; preclinical development; preclinical efficacy; public health emergency; response; safety study; safety testing; scale up; screening; small molecule; structured lipid; success; uptake; vaccine candidate; vaccine development; vaccine efficacy

Project Summary Opioid use disorders (OUD) are a national public health emergency with more than 115 fatal overdoses occurring each day in the USA. Annually, the economic burden of OUD is over US$78 billion. Several medications are available for treating OUD, but their access is limited and efficacy is often sub-optimal. It is thus urgent to develop new and affordable strategies to treat OUD. Immunopharmacotherapy has emerged as a promising treatment approach against OUD. In contrast to traditional pharmacotherapies involving pharmacological agonists and antagonists of the opioid receptors, immunopharmacotherapy relies on drug specific antibodies to bind the circulating drug molecules to reduce their distribution to the brain, and thus reducing opioid-induced behaviors and toxicity. Vaccination is likely the safer and more cost-effective immunopharmacotherapeutic intervention, due to the ability of vaccines to trigger innate and adaptive immune responses in patients to offer long lasting protection against OUD. Due to their selectivity, vaccines are not expected to interfere with endogenous opioids nor with opioids used in pain management or treatment of OUD. Furthermore, it is possible to combine vaccines with current medications for more effective OUD treatment because of the different mechanism of action. Current anti-opioid vaccine candidates are primarily conjugate vaccines (opioid hapten-carrier protein conjugates) delivered in adjuvants for immune recognition. Although these conjugate vaccines have shown promising pre- clinical efficacy and selectivity against OUD, it is critical to test novel immunization platforms that may further improve vaccine efficacy against OUD. Hence, the goal of this project is to fabricate novel nanoparticle-based vaccines against OUD, which will likely lead to an effective immune response against the target opioid by offering these unique features: 1) efficient presentation of B cell and T cell epitopes, 2) improved uptake of vaccine particles by immune cells, and 3) incorporation of molecular adjuvants to promote a synergistic activation of adaptive immune pathways. The innovation of this project involves merging Dr. Zhang's uniquely structured lipid- polymer nanocarriers with Dr. Pravetoni's well-established opioid-based hapten series and pre-clinical platform to identify vaccine candidates. Development will be staggered across UG3/UH3 phases, and we expect to identify lead formulations of nanovaccines that offer protection against either oxycodone, fentanyl, or both at once. The broad impact of this project resides in the rational design of nanoparticle-based vaccines that are safe and effective against opioids. This novel nanoparticle-based immunization strategy can be applied to the development of next-generation vaccines against a range of OUD and other substance use disorders.

项目概要 阿片类药物使用障碍 (OUD) 是一项全国性公共卫生紧急事件，已发生超过 115 起致命的过量用药事件 在美国的每一天。每年，OUD 的经济负担超过 780 亿美元。几种药物是 可用于治疗 OUD，但其获取途径有限且疗效往往不是最佳。因此迫切需要开发 治疗 OUD 的新且负担得起的策略。免疫药物疗法已成为一种有前途的治疗方法 反对 OUD 的方法。与涉及药理学激动剂和药物的传统药物疗法相比 阿片受体拮抗剂，免疫药物疗法依靠药物特异性抗体来结合 循环药物分子以减少其在大脑中的分布，从而减少阿片类药物引起的行为 和毒性。疫苗接种可能是更安全、更具成本效益的免疫药物治疗干预措施， 由于疫苗能够触发患者的先天性和适应性免疫反应，从而提供长期持续的免疫反应 针对 OUD 的保护。由于其选择性，疫苗预计不会干扰内源性阿片类药物 也不与用于疼痛管理或 OUD 治疗的阿片类药物一起使用。此外，还可以将疫苗联合使用。 由于作用机制不同，与现有药物相比，可以获得更有效的 OUD 治疗。当前的 候选抗阿片疫苗主要是结合疫苗（阿片半抗原载体蛋白结合物） 以佐剂形式递送以进行免疫识别。尽管这些结合疫苗已显示出有希望的预 针对 OUD 的临床疗效和选择性，测试新型免疫平台至关重要，这可能会进一步 提高针对 OUD 的疫苗功效。因此，该项目的目标是制造新型纳米颗粒 针对 OUD 的疫苗，这可能会通过提供针对目标阿片类药物的有效免疫反应 这些独特的功能：1) B 细胞和 T 细胞表位的有效呈递，2) 改善疫苗的吸收 免疫细胞颗粒，以及3）掺入分子佐剂以促进协同激活 适应性免疫途径。该项目的创新之处在于融合了张博士独特结构的脂质- 聚合物纳米载体与 Pravetoni 博士成熟的基于阿片类药物的半抗原系列和临床前平台 以确定候选疫苗。开发将在 UG3/UH3 阶段交错进行，我们预计 确定纳米疫苗的主要配方，可提供针对羟考酮、芬太尼或两者的保护 一次。该项目的广泛影响在于合理设计安全的纳米颗粒疫苗 并有效对抗阿片类药物。这种基于纳米粒子的新型免疫策略可应用于 开发针对一系列 OUD 和其他物质使用障碍的下一代疫苗。