Multivalent Vaccine for Opiate Addiction

用于阿片成瘾的多价疫苗

基本信息

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
项目类别：
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

项目摘要

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）：针对阿片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感知到的缺点，导致可接受性较低。因此，绝大多数阿片类药物成瘾者或滥用者没有接受针对这种疾病的药物治疗。额外的治疗选择可能会增加对治疗感兴趣的阿片类药物使用者的数量。这项研究的总体目标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，并且几种海洛因疫苗已在动物模型中显示出希望。将这种方法应用于治疗阿片成瘾的临床应用面临的挑战包括：1）提供针对各种常见滥用阿片的功效，2）避免封锁潜在医疗用途所需的关键阿片，以及3）提供足够的抗体滴度来阻断阿片的影响。成瘾者使用大剂量的阿片类药物。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制剂，从而减弱多种阿片制剂的作用，同时避免阻断非靶向阿片制剂。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、缺乏激动剂作用（对于那些真正或感知到反对服用成瘾药物的人）、新颖的作用机制以及联合用药的可能性与现有药物一起使用以增强依从性或疗效，并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迭代、集成的开发步骤，以识别和评估候选 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。目标 2 将表征各个免疫原的免疫原性，并选择最有效的免疫原来配制为单一 MOpV。目标 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，鉴定先导 MOpV，并测试免疫原可以组合成单个 MOpV 而不会丧失活性的假设。目标 4 将描述 MOpV 在第二个物种（大鼠）中在一定阿片剂量范围内以及急性和重复给药期间对阿片药代动力学的影响。目标 5 将测试 MOpV 在阻断大鼠（一种关键行为模型）阿片类药物自我给药方面的功效。目标 6 将评估 MOpV 安全性。这些数据将为阿片疫苗的可行性以及使用多价疫苗的新策略提供全面的测试。公共卫生相关性：海洛因成瘾对公共健康具有深远的不利影响。除了扰乱吸毒者、家人和朋友的生活外，它还与犯罪、医疗保健支出增加有关，并且静脉注射药物滥用大大促进了艾滋病毒/艾滋病、丙型肝炎和其他感染的传播。处方阿片剂的滥用也已成为一个主要的公共卫生问题，目前在美国，这些阿片剂的使用量比海洛因还要多，而且大量使用者上瘾。针对阿片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感知到的缺点，导致可接受性较低。因此，绝大多数阿片类药物成瘾者或滥用者没有接受针对这种疾病的药物治疗。替代药物可以提供更多的治疗选择，可能会增加选择并继续接受治疗的成瘾者数量。已经开发出针对尼古丁或可卡因成瘾的疫苗，疫苗接种可以刺激抗体的产生，这些抗体可以与成瘾药物结合并减少到达大脑的量。这会降低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进行作为成瘾治疗的临床试验。在动物身上的初步研究表明，海洛因疫苗也可能具有类似的效果。开发阿片类疫苗的一个挑战是，有许多不同的阿片类药物可以相互替代，因此疫苗需要阻止其中的每一种。我们建议开发一种阿片类疫苗，可以阻止大多数常见滥用的阿片类药物的作用。这将通过服用 3 种或更多单独的疫苗来实现，每种疫苗都会阻止某些阿片类药物，并将它们组合成一种“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中的阿片效应，并提供适合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类成瘾者或滥用者提供另一种类型的药物，或者可能在现有药物的基础上使用以增强其疗效。

项目成果

期刊论文数量（9）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

A Fentanyl Vaccine Alters Fentanyl Distribution and Protects against Fentanyl-Induced Effects in Mice and Rats.

芬太尼疫苗改变芬太尼的分布并防止芬太尼在小鼠和大鼠中引起的影响。

DOI：
发表时间：
2019
期刊：
影响因子：
0
作者：
Raleigh, Michael D;Baruffaldi, Federico;Peterson, Samantha J;Le Naour, Morgan;Harmon, Theresa M;Vigliaturo, Jennifer R;Pentel, Paul R;Pravetoni, Marco
通讯作者：
Pravetoni, Marco

An oxycodone conjugate vaccine elicits drug-specific antibodies that reduce oxycodone distribution to brain and hot-plate analgesia.

羟考酮结合疫苗可引发药物特异性抗体，减少羟考酮在大脑中的分布和热板镇痛。

DOI：
发表时间：
2012-04
期刊：
影响因子：
0
作者：
Pravetoni, M;Le Naour, M;Harmon, T M;Tucker, A M;Portoghese, P S;Pentel, P R
通讯作者：
Pentel, P R

Effect of currently approved carriers and adjuvants on the pre-clinical efficacy of a conjugate vaccine against oxycodone in mice and rats.

目前批准的载体和佐剂对羟考酮结合疫苗在小鼠和大鼠中的临床前功效的影响。

DOI：
发表时间：
2014
期刊：
影响因子：
3.7
作者：
Pravetoni, Marco;Vervacke, Jeffrey S;Distefano, Mark D;Tucker, Ashli M;Laudenbach, Megan;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.

生物样品中海洛因、6-单乙酰吗啡和吗啡的稳定性以及大鼠药代动力学样品延迟分析的 LC-MS 测定验证。

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.

羟考酮结合疫苗对大鼠羟考酮自我给药和羟考酮诱导的脑基因表达的影响。