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.

抽象的 美国正在经历阿片类药物危机，这是公共卫生紧急情况。 2016年，阿片类药物过量 死亡人数超过40,000。海洛因过量造成15,000次阿片类药物死亡和处方 与阿片类药物有关的死亡为17,000。解决这一危机的一种新颖方法是通过发展 海洛因/阿片类疫苗。我们开发了一种候选疫苗，该疫苗影响粘结海洛因/阿片类药物的抗体 注射并随后防止药物越过血脑屏障并与 大脑的µ阿片类接收器。根据2012年的Nida Arvant Garde奖，我们完成了临床前测试 小鼠和大鼠的疫苗候选者，证明它们受到皮下和静脉内的保护 海洛因挑战。我们正在进行的耐用性研究表明抗体滴度和保护效率 最后一次疫苗接种后6个月维持。对海洛因和其他抗体的约束性亲和力 滥用的处方阿片类药物非常紧（<0.1-15 nm）。我们建议推进我们的发展 通过进行I/IIA期人类临床试验进行疫苗候选者。在UG3机制下，疫苗合成 将进行非临床研究。我们将在CGMP下制造海洛因触发，6-AMHAP和 购买临床级Tetanius毒素和接头。陆军脂质体组（ALF43）和Alhydrogel® 佐剂已在CGMP下制造和瓶装，可用于使用。疫苗成分将 在啮齿动物中对海洛因挑战的免疫原性和效率进行测试。疫苗效力测定将是 发达。将组装一个Ind档案，并将完成预印度会议。 GLP兔子 将进行药理学毒理学研究。在UH3机制下，将进行临床试验 在纽约州立大学医科大学。试验将有4个组件。组件1将注册健康 18-49岁的志愿者没有海洛因使用障碍史； 22疫苗接收者和12个安慰剂 收件人。他们将在第0、3、6和14周的肌肉内路线接种疫苗。探索疫苗 安全将是主要目标。免疫原性将通过抗体在多个时间点进行评估 确定。将在同一时间点收集用于microRNA测定的唾液。组件2将 注册44（22疫苗和22个安慰剂）健康成年人18-49具有海洛因使用障碍史并记录下来 禁欲不少于6个月。组件3将包括一个从组件1到的志愿者的子集 进行血浆和白细胞释放，然后参与低剂量吗啡挑战和保护 评估。组件4将从等离子体和白细胞中采用产品，并进行被动转移和 海洛因挑战实验在小鼠和大鼠模型中。将确定原则的疫苗证明。