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.

项目摘要 阿片类药物使用障碍(OUD)是一种全国性的突发公共卫生事件，超过115起致命的过量事件 在美国每天都有。每年，OUD的经济负担超过780亿美元。有几种药物是 可用于OUD治疗，但他们获得的机会有限，疗效往往不佳。因此，迫切需要发展 治疗OUD的新的、负担得起的策略。免疫药物疗法已经成为一种很有前途的治疗方法 接近乌德。与涉及药物激动剂和 阿片受体的拮抗剂，免疫药物治疗依赖于药物特异性抗体结合 循环药物分子以减少它们在大脑中的分布，从而减少阿片类药物诱导的行为 和毒性。接种疫苗可能是更安全和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和获得性免疫反应，从而提供持久的 针对OUD的保护。由于疫苗的选择性，预计疫苗不会干扰内源性阿片类药物 也没有阿片类药物用于止痛或治疗OUD。此外，还有可能将疫苗 由于作用机制的不同，目前的药物治疗更有效。当前 抗阿片类药物疫苗候选主要是结合疫苗(阿片类半抗原载体蛋白结合物)。 在免疫识别佐剂中提供。尽管这些结合疫苗已经显示出很有希望的预 针对OUD的临床有效性和选择性，关键是测试新的免疫平台，这可能会进一步 提高针对OUD的疫苗效力。因此，本项目的目标是制备新型的基于纳米颗粒的 针对OUD的疫苗，这将可能导致对目标阿片类药物的有效免疫反应 这些独特的特征：1)高效地呈现B细胞和T细胞表位，2)提高疫苗的接种率 免疫细胞的颗粒，以及3)分子佐剂的掺入促进协同激活 适应性免疫途径。这个项目的创新之处在于融合了张博士独特的结构脂质-- 具有Pravetoni博士成熟的阿片类药物半抗原系列和临床前平台的聚合物纳米载体 以确定候选疫苗。发展将在UG3/UH3阶段交错进行，我们预计 识别针对羟考酮、芬太尼或两者都提供保护的纳米疫苗的主要配方，请参见 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。 对阿片类药物有效。这种新型的基于纳米颗粒的免疫策略可以应用于 针对一系列疾病和其他物质使用障碍的下一代疫苗的开发。