Vaccines for Sustainable Therapy of Opiate Addiction

用于阿片成瘾可持续治疗的疫苗

• 批准号: 7892450
• 负责人: FRANK M ORSON
• 金额: $ 36.01万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-15 至 2013-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7892450
• 关键词: 6-O-monoacetylmorphine; AODD relapse; Absence of pain sensation; Adjuvant; Affinity; Aluminum Hydroxide; American; Animal Model; Animals; Antibodies; Antibody Affinity; Antibody Formation; Australia; Behavior; Behavioral; Binding; Biological Models; Blood - brain barrier anatomy; Blood Circulation; Blood-Borne Pathogens; Brain; Carrier Proteins; Characteristics; Chemicals; China; Cholera Toxin; Chronic; Clinical; Clinical Research; Cocaine; Codeine; Collaborations; Conjugate Vaccines; Country; Data; Dependence; Developing Countries; Development; Dose; Drug Carriers; Drug Kinetics; Drug Prescriptions; Drug abuse; Drug usage; Economics; Effectiveness; Emulsions; Future; HIV; Haptens; Health; Heroin; Heroin Abuse; Hour; Human; Immune Sera; Immune response; Immunization; Immunoglobulin G; Immunologic Memory; India; Individual; Injection of therapeutic agent; Life; Link; Liver; Measures; Membrane Proteins; Methamphetamine; Methods; Modeling; Monitor; Morphine; Morphine Dependence; Morphine Derivatives Including Cocaine; Motor Activity; Mus; Narcotics; Neisseria meningitidis; Neuraxis; Neurotransmitters; Nicotine; Oils; Oligonucleotides; Opiate Addiction; Opiates; Oral; Penetration; Pharmaceutical Preparations; Pharmacodynamics; Physiological; Positioning Attribute; Prevention approach; Prodrugs; Proteins; Publishing; Rattus; Relapse; Research; Research Personnel; Rodent Model; Role; Route; Russia; Screening procedure; Self Administration; Series; Site; Speed; Supplementation; T cell response; Target Populations; Testing; Therapeutic; TiterMax; Universities; Vaccinated; Vaccination; Vaccine Adjuvant; Vaccine Design; Vaccines; Water; Work; addiction; attenuation; candidate selection; cross reactivity; design; disorder later incidence prevention; drug craving; drug reinforcement; effective therapy; esterase; hydroxyl group; interest; intravenous injection; methadone clinic/center; monophosphoryl lipid A; morphine-6-glucuronide; mouse model; normorphine; novel; opioid abuse; phase 2 study; preclinical study; programs; protein complex; public health relevance; response; small molecule; social; success; theories; therapeutic vaccine; tool; treatment program; vaccine candidate; vaccine development; vaccine evaluation

DESCRIPTION (provided by applicant): Opiate abuse/dependence has profound social and economic effects in all parts of the world. Intravenous injection is the major route of illicit opiate drug administration in most countries, although abuse of oral prescription drugs has been recently increasing. While methadone clinics and other treatment programs can be effective, the expense of the support programs and medications can inhibit broad application of these methods to the target population, especially in less developed nations, and can be quite controversial in others. Without more effective treatment or prevention approaches for drug abuse, addiction to narcotics is very likely to accelerate further. An especially attractive alternative approach against opiate addiction in this context is immunization, a potentially powerful tool in assisting individuals to stop their abuse of these substances. Although there are many forms of opiate abuse, it is essential to focus experimental efforts for vaccine development on a limited number of specific agents to establish the effectiveness of this approach. Any effective vaccine for heroin will have to elicit high levels of antibodies that bind heroin, morphine, and other active metabolites, since concentrations of pharmacologically active opiates exceed the usual amounts of specific antibody. As our preliminary data shows, the outer membrane protein complex (OMPC) of Neisseria meningitidis is particularly attractive as a carrier for the morphine conjugate vaccine, since it elicits early, high level responses to the drug. The antibody response and the inhibition of morphine pharmacological effects can be directly evaluated in rodent model systems, permitting the rapid development of candidate vaccines. This proposal focuses on therapeutic heroin/morphine vaccines with these hypotheses: 1) Screening morphine linked to different carrier proteins or to a lipopeptide construct will allow selection of a vaccine that, along with appropriate adjuvant(s), can rapidly elicit a sufficient quantity and quality of specific antibody to block the pharmacological activity of heroin and its active metabolites. 2) The quality and quantity of the antibodies induced by these vaccines that can block opiate associated analgesia will also block heroin induced locomotor activity and reinstatement of heroin self administration in the rat model. Morphine will be conjugated to two highly effective protein carriers: OMPC and cholera toxin b (CTB). These conjugate vaccines will be compared with a novel self-adjuvanting lipopeptide vaccine prepared by D. C. Jackson (University of Melbourne, Australia). A panel of adjuvants compatible with human use will be examined to maximize the antibody quantity, quality (affinity), and persistence as well as the inhibition of opiate induced analgesia, locomotor activity, and reinstatement of drug self-administration. Successful completion of this project will continue the collaboration between American and Australian investigators that will be ideally positioned to get a vaccine quickly into clinical development studies. PUBLIC HEALTH RELEVANCE: Opiate abuse/dependence has had profound social and economic effects in all parts of the world. Intravenous injection is the dominant route of illicit opiate drug use, magnifying the health consequences of addiction through the spread of various blood borne pathogens. An especially attractive alternative approach to help treat opiate addiction is vaccination against these drugs, which could become a powerful tool in assisting individuals to stop their abuse of these substances. This research will develop such vaccines by attaching morphine to carrier molecules and testing immunization conditions that will stimulate high levels of antibody to block the effects of heroin and morphine on relapse to drug self administration in the mouse model of opiate abuse.

描述（由申请人提供）：阿片类药物滥用/依赖在世界各地都有深刻的社会和经济影响。静脉注射是大多数国家非法阿片类药物给药的主要途径，尽管口服处方药的滥用最近有所增加。虽然美沙酮诊所和其他治疗方案可能是有效的，但支持方案和药物的费用可能会抑制这些方法在目标人群中的广泛应用，特别是在欠发达国家，并且在其他国家可能会引起相当大的争议。如果不对药物滥用采取更有效的治疗或预防办法，吸毒成瘾很可能会进一步加速。在这种情况下，一种特别有吸引力的防止阿片剂成瘾的替代办法是免疫接种，这是协助个人停止滥用这些物质的一个潜在的有力工具。虽然阿片类药物滥用有多种形式，但必须将疫苗开发的实验工作集中在数量有限的特定制剂上，以确定这种方法的有效性。任何有效的海洛因疫苗都必须能激发出高水平的抗体，这些抗体能与海洛因、吗啡和其他活性代谢物结合，因为具有免疫活性的阿片类药物的浓度超过了特异性抗体的通常含量。如我们的初步数据所示，脑膜炎奈瑟氏菌的外膜蛋白复合物（OMPC）作为吗啡缀合物疫苗的载体特别有吸引力，因为它引起对药物的早期高水平应答。抗体反应和吗啡药理学作用的抑制可以直接在啮齿动物模型系统中进行评价，从而允许候选疫苗的快速开发。该建议集中于具有这些假设的治疗性海洛因/吗啡疫苗：1）筛选与不同载体蛋白或脂肽构建体连接的吗啡将允许选择疫苗，所述疫苗与适当的佐剂一起沿着，可以快速地引发足够数量和质量的特异性抗体以阻断海洛因及其活性代谢物的药理学活性。2)由这些疫苗诱导的抗体的质量和数量可以阻断阿片相关镇痛，也将阻断海洛因诱导的运动活动和海洛因自我给药在大鼠模型中的恢复。吗啡将与两种高效的蛋白质载体结合：OMPC和霍乱毒素B（CT B）。将这些偶联疫苗与D. C.杰克逊（澳大利亚墨尔本大学）。将检查一组与人类使用相容的佐剂，以最大化抗体数量、质量（亲和力）和持久性以及抑制阿片诱导的镇痛、自主活动和恢复药物自我施用。该项目的成功完成将继续美国和澳大利亚研究人员之间的合作，这将是理想的定位，以获得疫苗迅速进入临床开发研究。 与公共卫生的关系：阿片类药物滥用/依赖在世界各地都产生了深刻的社会和经济影响。静脉注射是非法使用阿片类药物的主要途径，通过传播各种血液传播的病原体，扩大了成瘾的健康后果。帮助治疗阿片类药物成瘾的一种特别有吸引力的替代方法是针对这些药物的疫苗接种，这可能成为帮助个人停止滥用这些药物的有力工具。这项研究将通过将吗啡附着在载体分子上并测试免疫条件来开发这种疫苗，这种免疫条件将刺激高水平的抗体，以阻断海洛因和吗啡对阿片类药物滥用小鼠模型中药物自我给药复发的影响。