Multivalent Vaccine for Opiate Addiction

用于阿片成瘾的多价疫苗

• 批准号: 8310243
• 负责人: PAUL R PENTEL
• 金额: $ 43.32万
• 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 2014-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8310243
• 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; 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; 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; prescription opiate; 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且有效的，但每种药物都有实际或可感知的缺点，导致低可接受性。因此，绝大多数阿片类药物成瘾者或滥用者没有接受药物治疗。额外的治疗方案可能会增加对治疗感兴趣的阿片剂使用者的人数。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，一些海洛因疫苗已在动物模型中显示出希望。将这种方法转化为治疗阿片类成瘾的临床应用所面临的挑战包括：1)提供针对广泛的常见滥用阿片类药物的疗效；2)避免阻断潜在医疗用途所需的关键阿片类药物；3)提供足够的抗体滴度来阻断成瘾者使用大剂量阿片类药物的影响。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，可以减弱多种阿片的作用，同时避免阻断非靶向阿片。作为一种额外的治疗选择，阿片疫苗的潜在优势包括作用持续时间长、没有激动剂作用（对于那些对服用成瘾性药物有实际或被认为有反对意见的人）、一种新的作用机制和与现有药物联合使用以增强依从性或疗效的可能性，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使用。免疫原将经历一系列反复、综合的开发步骤，以确定和评估候选mopv的疗效。目的1将设计合适的半抗原，并通过使用各种连接物、载体蛋白和佐剂来优化功效。目标2将描述单个免疫原的免疫原性，并选择最有效的免疫原配制成单一的MOpV。目的3将提供小鼠药代动力学和行为（热板镇痛）功效的快速通量筛选，鉴定一种先导MOpV，并验证免疫原可以组合成一种MOpV而不丧失活性的假设。目标4将描述MOpV在阿片类药物剂量范围内以及急性和重复给药期间对第二种物种（大鼠）阿片类药物代动力学的影响。目的5将测试MOpV阻断大鼠阿片类药物自我给药的有效性，这是一个关键的行为模型。目标6将评估MOpV的安全性。这些数据将提供对阿片疫苗可行性的全面测试，以及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。除了扰乱吸毒者、家人和朋友的生活外，它还与犯罪、增加保健支出和静脉注射药物滥用有关，大大加剧了艾滋病毒/艾滋病、丙型肝炎和其他感染的传播。处方阿片类药物的滥用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了海洛因，而且有相当数量的使用者上瘾。阿片类药物成瘾或滥用的药物治疗是可用的和有效的，但每一个都有实际的或感知的缺点，导致低可接受性。因此，绝大多数鸦片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，可能会增加成瘾者选择并坚持治疗的人数。针对尼古丁或可卡因成瘾的疫苗已经开发出来，通过接种疫苗刺激抗体的产生，这种抗体可以结合成瘾药物并减少到达大脑的数量。这降低了药物的奖励或愉悦效果。三种尼古丁疫苗（针对吸烟者）和一种可卡因疫苗目前正在临床试验中，作为成瘾治疗。在动物身上进行的初步研究表明，海洛因疫苗可能同样有效。研制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，因此疫苗需要阻断每一种阿片类药物。我们建议开发一种阿片疫苗，它可以阻断大多数常被滥用的阿片的作用。这将通过服用3种或更多的单独疫苗来实现，每种疫苗都能阻断某些阿片类药物，并将它们组合成一种单一的“多价”疫苗。我们的假设是，这种方法将安全有效地阻断小鼠或大鼠的阿片效应，并提供一种适合潜在临床开发的疫苗。这可以为那些认为现有选择无法接受的阿片成瘾者或滥用者提供一种额外的药物，或者可能在现有药物之外使用，以提高其疗效。

项目成果

Reduced antinociception of opioids in rats and mice by vaccination with immunogens containing oxycodone and hydrocodone haptens.

• DOI: 10.1021/jm3013745
• 发表时间: 2013-02-14
• 期刊: JOURNAL OF MEDICINAL CHEMISTRY
• 影响因子: 7.3
• 作者: Pravetoni, Marco;Le Naour, Morgan;Tucker, Ashli M.;Harmon, Theresa M.;Hawley, Tara M.;Portoghese, Philip S.;Pentel, Paul R.
• 通讯作者: Pentel, Paul R.

Stability of heroin, 6-monoacetylmorphine, and morphine in biological samples and validation of an LC-MS assay for delayed analyses of pharmacokinetic samples in rats.

• DOI: 10.1016/j.jpba.2012.10.033
• 发表时间: 2013-02-23
• 期刊: JOURNAL OF PHARMACEUTICAL AND BIOMEDICAL ANALYSIS
• 影响因子: 3.4
• 作者: Jones, Jessica M.;Raleigh, Michael D.;Pentel, Paul R.;Harmon, Theresa M.;Keyler, Daniel E.;Remmel, Rory P.;Birnbaum, Angela K.
• 通讯作者: Birnbaum, Angela K.

Effects of an oxycodone conjugate vaccine on oxycodone self-administration and oxycodone-induced brain gene expression in rats.

• DOI: 10.1371/journal.pone.0101807
• 发表时间: 2014
• 期刊: PloS one
• 影响因子: 3.7
• 作者: Pravetoni M;Pentel PR;Potter DN;Chartoff EH;Tally L;LeSage MG
• 通讯作者: LeSage MG

Pharmacokinetic correlates of the effects of a heroin vaccine on heroin self-administration in rats.

• DOI: 10.1371/journal.pone.0115696
• 发表时间: 2014
• 期刊: PloS one
• 影响因子: 3.7
• 作者: Raleigh MD;Pentel PR;LeSage MG
• 通讯作者: LeSage MG

Co-administration of morphine and oxycodone vaccines reduces the distribution of 6-monoacetylmorphine and oxycodone to brain in rats.

• DOI: 10.1016/j.vaccine.2012.04.101
• 发表时间: 2012-06-29
• 期刊: VACCINE
• 影响因子: 5.5
• 作者: Pravetoni, M.;Raleigh, M. D.;Le Naour, M.;Tucker, A. M.;Harmon, T. M.;Jones, J. M.;Birnbaum, A. K.;Portoghese, P. S.;Pentel, P. R.
• 通讯作者: Pentel, P. R.