A Phase I/IIa Clinical Trial Testing the Safety and Immunogenicity of a Heroin Vaccine and its Efficacy Against Morphine Challenge.

I/IIa 期临床试验测试海洛因疫苗的安全性和免疫原性及其对抗吗啡挑战的功效。

• 批准号: 9789862
• 负责人: Gary R. Matyas
• 金额: $ 379.73万
• 依托单位: HENRY M. JACKSON FDN FOR THE ADV MIL/MED
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-30 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9789862
• 关键词: Abstinence; Address; Adjuvant; Adult; Advanced Development; Affinity; Alhydrogel; Aluminum Hydroxide; Animals; Antibodies; Antibody Affinity; Antibody titer measurement; Award; Basic Science; Binding; Bioethics; Biological Assay; Blood - brain barrier anatomy; Brain; Clinical; Clinical Investigator; Clinical Protocols; Clinical Trials; Cyclic GMP; Development; Disease; Dose; Enrollment; Ethics; Fentanyl; Formulation; Future; Haptens; Heroin; Heroin Abuse; Human; Immune; Immunoglobulin G; Injections; Institutional Review Boards; Intramuscular; Intravenous; Kinetics; Licensure; Lipid A; Liposomes; Measures; Medical; MicroRNAs; Modeling; Morals; Morphine; Mus; National Institute of Drug Abuse; Opioid; Oryctolagus cuniculus; Outcome; Outcomes Research; Pain Measurement; Pamphlets; Participant; Passive Transfer of Immunity; Pattern; Performance; Peripheral Blood Mononuclear Cell; Pharmaceutical Preparations; Pharmacology and Toxicology; Phase; Placebos; Plasma; Preclinical Testing; Protocols documentation; Rattus; Recording of previous events; Relapse; Research; Research Personnel; Rodent; Route; Safety; Saliva; Sampling; Serum; Specimen; Substance abuse problem; Testing; Tetanus Toxoid; Time; Translational Research; United States; United States Food and Drug Administration; Universities; Vaccinated; Vaccination; Vaccines; Vial device; addiction; base; cohort; cross reactivity; efficacy testing; experience; experimental study; genetic signature; healthy volunteer; heroin overdose; heroin use; immunogenicity; meetings; mu opioid receptors; novel; novel strategies; opioid epidemic; opioid mortality; polyclonal antibody; potency testing; prescription opioid; prescription opioid abuse; prevent; protective efficacy; public health emergency; repository; research clinical testing; safety testing; stability testing; subcutaneous; symposium; vaccine candidate; vaccine efficacy; vaccine safety; volunteer

Abstract The United States is experiencing an opioid crisis, which is a public health emergency. In 2016, opioid overdose deaths exceeded 40,000. Heroin overdose was responsible for 15,000 of the opioid deaths and prescription opioid-related deaths were 17,000. A novel approach to address this crisis is through the development of a heroin/opioid vaccine. We have developed a candidate vaccine which induces antibodies that bind heroin/opioid upon injection and, subsequently, prevent the drug from crossing the blood-brain barrier and interacting with the brain's µ-opioid receptor. Under a 2012, NIDA Avant Garde Award, we completed pre-clinical testing of the vaccine candidate in mice and rats demonstrating they were protected from subcutaneous and intravenous heroin challenge. Our ongoing durability studies have demonstrated that antibody titer and protective efficacy were maintained 6 months after the last vaccination. The binding affinities of the antibodies to heroin and other abused prescription opioids were very tight (<0.1-15 nM). We propose to advance the development of our vaccine candidate by conducting a Phase I/IIa human clinical trial. Under the UG3 mechanism, vaccine synthesis and nonclinical studies will be conducted. We will manufacture the heroin hapten, 6-AmHap, under cGMP, and purchase clinical grade tetanus toxoid and linker. Army Liposome Formulation (ALF43) and Alhydrogel® adjuvants have been manufactured and vialed under cGMP and are available for use. Vaccine components will be tested in rodents for immunogenicity and efficacy from heroin challenge. A vaccine potency assay will be developed. An IND dossier will be assembled and pre-IND meeting will be completed. A GLP rabbit pharmacology-toxicology study will be conducted. Under the UH3 mechanism, the clinical trial will be conducted at the SUNY Upstate Medical University. The trial will have 4 components. Component 1 will enroll healthy volunteers 18-49 years old without history of heroin use disorder; 22 vaccine recipients and 12 placebo recipients. They will be vaccinated by the intramuscular route at weeks 0, 3, 6, and 14. Exploring the vaccine's safety will be the primary objective. Immunogenicity will be assessed at multiple time points through antibody determinations. Saliva for microRNA determinations will be collected at the same time points. Component 2 will enroll 44 (22 vaccine and 22 placebo) healthy adults 18-49 with a history of heroin use disorder and documented abstinence for no less than 6 months. Component 3 will include a subset of volunteers from Component 1 to undergo plasma and leukopharesis and then participate in a low dose morphine challenge and protection assessment. Component 4 will take products from plasma and leukopharesis and conduct passive transfer and heroin challenge experiments in mice and rat models. The vaccine proof of principle will be established.

摘要 美国正在经历一场阿片类药物危机，这是一种公共卫生紧急情况。2016年，阿片类药物过量 死亡人数超过4万人。海洛因过量导致了15,000例阿片类药物死亡和处方 与阿片类药物有关的死亡人数为17,000人。解决这一危机的一种新方法是通过开发一种 海洛因/阿片疫苗。我们已经开发出一种候选疫苗，它可以诱导与海洛因/阿片类药物结合的抗体。 注射后，防止药物越过血脑屏障，并与 大脑的微阿片受体。根据2012年的NIDA Avant Garde奖，我们完成了 候选疫苗在小鼠和大鼠身上显示它们受到皮下和静脉注射的保护 海洛因挑战赛。我们正在进行的持久性研究表明，抗体效价和保护效果 在最后一次接种后6个月维持。海洛因和其他抗体的结合亲和力 滥用处方类阿片非常紧凑(&lt；0.1-15 NM)。我们建议推进我们的发展 通过进行I/IIa期人体临床试验获得候选疫苗。在UG3机制下，疫苗合成 并将进行非临床研究。我们将在cGMP下生产海洛因半抗原6-AMHap，并 购买临床级破伤风类毒素和链接物。陆军脂质体制剂(ALF43)和Alwater Gel® 佐剂已在cGMP下生产和包装，并可供使用。疫苗组件将 在啮齿类动物身上测试海洛因攻击的免疫原性和有效性。疫苗效力测试将是 发展起来的。将汇编IND档案，并完成IND前会议。一只普洛斯兔 将进行药理学-毒理学研究。在UH3机制下，将进行临床试验 在纽约州立大学北部医科大学。审判将由4个部分组成。组件1将健康注册 18-49岁无海洛因使用障碍史的志愿者；22名疫苗接受者和12名安慰剂 收件人。他们将在0、3、6和14周通过肌肉注射途径接种疫苗。 安全将是首要目标。将通过抗体在多个时间点评估免疫原性 决定。将在同一时间点收集用于microRNA检测的唾液。组件2将 招募44名(22名疫苗和22名安慰剂)18-49岁有海洛因使用障碍病史并有文件记录的健康成年人 禁欲不少于6个月。组件3将包括从组件1到组件1的志愿者子集 接受血浆和白细胞导入，然后参与小剂量吗啡的挑战和保护 评估。组件4将从血浆和白细胞导入中提取产品，并进行被动转移和 海洛因对小鼠和大鼠模型的挑战实验。疫苗的原则性证明将被确立。