Vaccines for Sustainable Therapy of Opiate Addiction

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。在大多数国家，静脉注射是非法给药阿片类药物的主要途径，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相当有争议。如果没有更有效的药物滥用治疗或预防办法，对麻醉品的上瘾很可能会进一步加速。在这方面，一个特别有吸引力的防止阿片类药物成瘾的替代办法是免疫接种，这可能是帮助个人停止滥用这些物质的有力工具。尽管阿片类药物的滥用形式多种多样，但必须将研制疫苗的实验工作重点放在数量有限的特定制剂上，以确定这一方法的有效性。任何有效的海洛因疫苗都必须引起结合海洛因、吗啡和其他活性代谢物的高水平抗体，因为具有药理活性的阿片类药物的浓度超过了特定抗体的通常量。正如我们的初步数据所示，脑膜炎奈瑟菌的外膜蛋白复合物（OMPC）作为吗啡结合疫苗的载体特别有吸引力，因为它能引起对药物的早期高水平反应。在啮齿类动物模型系统中，可以直接评估抗体反应和吗啡药理作用的抑制作用，从而可以快速开发候选疫苗。本建议的重点是治疗性海洛因/吗啡疫苗，其假设如下：1)筛选与不同载体蛋白或脂肽结构相关的吗啡，将允许选择一种疫苗，该疫苗与适当的佐剂一起，可以迅速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活性。2)阻断阿片相关镇痛的疫苗诱导的抗体的质量和数量也会阻断海洛因诱导的大鼠运动活动和海洛因自我给药的恢复。吗啡将与两种高效的蛋白质载体结合：OMPC和霍乱毒素b （CTB）。这些结合疫苗将与D. C. Jackson（澳大利亚墨尔本大学）制备的一种新型自佐剂脂肽疫苗进行比较。一组与人类使用相容的佐剂将被检查，以最大限度地提高抗体的数量、质量（亲和力）和持久性，以及抑制阿片类药物引起的镇痛、运动活动和恢复药物自我给药。这个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，这将为疫苗迅速进入临床开发研究提供理想的条件。

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.