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

摘要 美国正在经历阿片类药物危机，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15，000例阿片类药物死亡和处方 与类阿片有关的死亡人数为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/阿片类药物疫苗。我们已经开发出一种候选疫苗，它可以诱导结合海洛因/阿片类药物的抗体。 并且随后防止药物穿过血脑屏障并与药物相互作用。 大脑的μ-阿片受体。根据2012年NIDA先锋奖，我们完成了 在小鼠和大鼠中的候选疫苗，证明它们可以保护皮下和静脉注射 海洛因挑战我们正在进行的耐久性研究表明，抗体滴度和保护效力 在最后一次疫苗接种后维持6个月。抗体对海洛因和其他 滥用的处方阿片类药物非常紧张（<0.1-15 nM）。我们建议推动发展我们的 通过进行I/IIa期人体临床试验获得候选疫苗。在UG 3机制下，疫苗合成 将进行非临床研究。我们将在cGMP下生产海洛因半抗原6-AmHap， 购买临床级破伤风类毒素和连接剂。Army脂质体制剂（ALF 43）和Alhydrogel® 佐剂已经在cGMP下生产和装瓶，并且可供使用。疫苗成分将 在啮齿动物中测试海洛因激发的免疫原性和有效性。将进行疫苗效价测定， 开发将收集IND档案并完成IND前会议。GLP家兔 将进行药理学-毒理学研究。根据UH 3机制，将进行临床试验 在纽约州立大学北部医科大学。试验将包括4个部分。组件1将招募健康 志愿者18-49岁，无海洛因使用障碍史; 22名疫苗接种者和12名安慰剂 受惠人士将在第0、3、6和14周通过肌内途径接种。探索疫苗 安全将是首要目标。将在多个时间点通过抗体评估免疫原性 决心。将在相同的时间点收集用于microRNA测定的唾液。构成部分2将 招募44名（22名疫苗和22名安慰剂）健康成人，18-49岁，有海洛因使用障碍史，并记录 禁欲不少于6个月。组成部分3将包括组成部分1至10的一部分志愿者。 进行血浆和白细胞分离，然后参与低剂量吗啡攻击和保护 考核组件4将从血浆和白细胞分离中获取产物，并进行被动转移， 小鼠和大鼠模型中的海洛因攻击实验。将建立疫苗原理证明。

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.