Multivalent Vaccine for Opiate Addiction

用于阿片成瘾的多价疫苗

• 批准号: 7687413
• 负责人: PAUL R PENTEL
• 金额: $ 46.68万
• 依托单位: HENNEPIN HEALTHCARE RESEARCH INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-09-15 至 2013-09-14
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7687413
• 关键词: 6-O-monoacetylmorphine; AIDS/HIV problem; Absence of pain sensation; Acute; Adjuvant; Adverse effects; Agonist; Animal Model; Animals; Antibodies; Antibody Affinity; Antibody Formation; Antigens; Attenuated; Behavioral; Behavioral Model; Binding; Blood; Brain; Buprenorphine; Carrier Proteins; Chronic; Clinical; Clinical Trials; Cocaine; Cocaine Dependence; Codeine; Conjugate Vaccines; Crime; Data; Data Set; Developed Countries; Developing Countries; Development; Disease; Dose; Drug Formulations; Drug Kinetics; Drug Metabolic Detoxication; Family; Fentanyl; Friends; Goals; Haptens; Health; Health Expenditures; Hepatitis C; Heroin; Heroin Dependence; Hydrocodone; Hydromorphone; Immunologics; Individual; Infection; Intravenous Drug Abuse; Lead; Length; Life; Maintenance; Measures; Medical; Methadone; Morphine; Mus; Naloxone; Naltrexone; Narcotic Antagonists; Nicotine; Nicotine Dependence; Opiate Addiction; Opiates; Oxycodone; Oxymorphone; Pharmaceutical Preparations; Pharmacotherapy; Phase; Precipitation; Protein Binding; Public Health; Rattus; Research Infrastructure; Rodent; Role; Safety; Screening procedure; Self Administration; Series; Serum; Serum Proteins; Smoker; Specificity; Testing; Therapeutic; Translating; Vaccination; Vaccines; Withdrawal; Work; addiction; clinically relevant; design; drug reward; endogenous opioids; immunogenic; immunogenicity; improved; interest; meetings; morphine-6-glucuronide; novel; novel strategies; opioid abuse; pre-clinical; public health relevance; research study; response; treatment strategy; vaccine development; vaccine efficacy; vaccine evaluation; vaccine safety

DESCRIPTION (provided by applicant): Medication treatments for opiate addiction or abuse are available and effective, but each has real or perceived drawback that result in low acceptability. As a result, the vast majority of opiate addicts or abusers are not receiving pharmacotherapy for this disorder. Additional treatment options might increase the number of opiate users interested in treatment. The overall aim of this study is to develop and evaluate an opiate vaccine in rats as a potential treatment for opiate addiction or abuse. Vaccines which alter drug pharmacokinetics have shown substantial preclinical and preliminary clinical evidence of efficacy for nicotine and cocaine addiction, and several heroin vaccines have shown promise in animal models. Challenges for translating this approach to clinical use for opiate addiction include 1) providing efficacy against the wide range of commonly abused opiates, 2) avoiding blockade of key opiates needed for potential medical use, and 3) providing sufficient antibody titers to block the effects of the large doses of opiates used by addicts. We hypothesize that a multivalent opiate vaccine (MOpV) consisting of 3 immunogens, each targeting a specific group of structurally related opiates, can be designed which will attenuate the effects of a broad range of opiates yet avoid blocking non-targeted opiates. Potential advantages of an opiate vaccine, as an additional treatment option, include a long duration of action, lack of agonist effects (for those with real or perceived objections to taking an addictive medication), a novel mechanism of action and the possibility of being combined with existing medications to augment compliance or efficacy, and use in developing countries which lack the infrastructure needed to deliver agonist or partial agonist treatment. Immunogens will undergo an iterative, integrated series of developmental steps to identify and evaluate the efficacy of candidate MOpVs. Aim 1 will design appropriate haptens and optimize efficacy through the use of a variety of linkers, carrier proteins and adjuvants. Aim 2 will characterize the immunogenicity of individual immunogens and select the most effective for formulation into a single MOpV. Aim 3 will provide rapid-throughput screening of pharmacokinetic and behavioral (hot plate analgesia) efficacy in mice, identify a lead MOpV, and test the hypothesis that immunogens can be combined into a single MOpV without loss of activity. Aim 4 will characterize the effects of MOpV on opiate pharmacokinetics in a second species (rats) over a range of opiate doses and during both acute and repeated drug dosing. Aim 5 will test MOpV efficacy in blocking opiate self-administration in rats, a key behavioral model. Aim 6 will evaluate MOpV safety. These data will provide a comprehensive test of opiate vaccine feasibility, and the novel strategy of using a multivalent vaccine. PUBLIC HEALTH RELEVANCE: Heroin addiction has profound adverse effects on public health. In addition to disrupting the lives of the addict, family and friends, it is associated with crime, increased health care expenditures, and intravenous drug abuse contributes substantially to the spread of HIV/AIDS, hepatitis C and other infections. Abuse of prescription opiates has also emerged as a major public health concern, with more use of these opiates currently in the U.S. than heroin, and a substantial number of users becoming addicted. Medication treatments for opiate addiction or abuse are available and effective, but each has real or perceived drawback that result in low acceptability. As a result, the vast majority of opiate addicts or abusers are not receiving medication treatment for this disorder. Alternative medications, which could provide a greater choice of therapeutic options, might increase the number of addicts electing and staying in treatment. Vaccines have been developed for nicotine or cocaine addiction whereby vaccination stimulates the production of antibodies that can bind the addictive drug and reduce the amount that reaches brain. This reduces the drug's rewarding or pleasurable effects. Three nicotine vaccines (for smokers) and one cocaine vaccine are currently in clinical trials as addiction treatments. Initial work in animals suggests that a heroin vaccine could be similarly effective. One challenge in developing an opiate vaccine is that there are many different opiates that can substitute for each other, so that a vaccine would need to block each of these. We propose to develop an opiate vaccine which can block the effects of most of the opiates that are commonly abused. This will be accomplished by taking 3 or more individual vaccines, each of which blocks certain opiates, and combining them into a single "multivalent" vaccine. Our hypothesis is that this approach will provide safe and effective blockade of opiate effects in mice or rats, and provide a vaccine that is suitable for potential clinical development. This could provide an additional type of medication for those opiate addicts or abusers who find the currently available options unacceptable, or possibly for use in addition to existing medications to enhance their efficacy.

描述（由申请人提供）：阿片类药物成瘾或滥用的药物治疗是可用的和有效的，但每一种都有真实的或可感知的缺点，导致可接受性低。因此，绝大多数阿片剂成瘾者或滥用者没有接受这种疾病的药物治疗。其他治疗选择可能会增加对治疗感兴趣的阿片剂使用者人数。本研究的总体目的是开发和评估大鼠阿片疫苗作为阿片成瘾或滥用的潜在治疗方法。改变药物药代动力学的疫苗已经显示出对尼古丁和可卡因成瘾有效的大量临床前和初步临床证据，并且几种海洛因疫苗已经在动物模型中显示出希望。将这种方法转化为阿片类药物成瘾的临床应用的挑战包括：1）提供针对广泛的常滥用阿片类药物的功效，2）避免阻断潜在医疗用途所需的关键阿片类药物，以及3）提供足够的抗体滴度以阻断成瘾者使用的大剂量阿片类药物的作用。我们假设可以设计一种由3种免疫原组成的多价阿片疫苗（MOpV），每种免疫原针对一组特定的结构相关的阿片类药物，这将减弱广泛的阿片类药物的作用，但避免阻断非靶向阿片类药物。阿片类疫苗作为一种额外的治疗选择的潜在优势包括作用持续时间长，缺乏激动剂效应（对于那些对服用成瘾药物有真实的或感知的反对的人），一种新的作用机制和与现有药物组合以增加依从性或功效的可能性，以及在缺乏提供激动剂或部分激动剂治疗所需基础设施的发展中国家的使用。免疫原将经历一系列迭代的综合开发步骤，以鉴定和评价候选MOpV的功效。目标1将设计合适的半抗原，并通过使用各种接头，载体蛋白和佐剂来优化功效。目的2将表征单个免疫原的免疫原性，并选择最有效的用于配制成单个MOpV。目的3将提供小鼠中药代动力学和行为（热板镇痛）功效的快速通量筛选，鉴定先导MOpV，并测试免疫原可以组合成单一MOpV而不丧失活性的假设。目的4将描述在阿片剂量范围内以及在急性和重复给药期间，MOpV对第二种属（大鼠）中阿片药代动力学的影响。目的5将测试MOpV在大鼠中阻断阿片剂自我给药的功效，这是一种关键的行为模型。目标6将评价MOpV安全性。这些数据将提供一个全面的测试阿片类疫苗的可行性，和使用多价疫苗的新策略。公共卫生相关性：海洛因成瘾对公共卫生有深远的不利影响。除了扰乱吸毒成瘾者、家人和朋友的生活外，它还与犯罪、增加保健开支和静脉注射吸毒有关，大大助长了艾滋病毒/艾滋病、丙型肝炎和其他感染的传播。滥用处方阿片类药物也已成为一个主要的公共卫生问题，目前在美国，这些阿片类药物的使用量超过海洛因，大量使用者成瘾。阿片类药物成瘾或滥用的药物治疗是可用的和有效的，但每一种都有真实的或可感知的缺点，导致可接受性低。因此，绝大多数阿片类药物成瘾者或滥用者没有接受这种疾病的药物治疗。替代药物可以提供更多的治疗选择，可能会增加选择和坚持治疗的成瘾者数量。已经开发了用于尼古丁或可卡因成瘾的疫苗，其中疫苗接种刺激抗体的产生，所述抗体可以结合成瘾药物并减少到达大脑的量。这降低了药物的奖励或愉悦效果。三种尼古丁疫苗（用于吸烟者）和一种可卡因疫苗目前正在临床试验中作为成瘾治疗。在动物身上的初步研究表明，海洛因疫苗可能具有类似的效果。开发阿片类药物疫苗的一个挑战是，有许多不同的阿片类药物可以相互替代，因此疫苗需要阻断其中的每一种。我们建议研制一种鸦片剂疫苗，它可以阻断大多数经常被滥用的鸦片剂的作用。这将通过服用3种或更多种单独的疫苗来实现，每种疫苗都能阻断某些阿片类药物，并将它们组合成单一的“多价”疫苗。我们的假设是，这种方法将提供安全有效的阻断阿片类药物在小鼠或大鼠中的作用，并提供一种适合于潜在临床开发的疫苗。这可以为那些认为目前可用的选择不可接受的阿片剂成瘾者或滥用者提供另一种药物，或者可能在现有药物之外使用，以提高其疗效。