Development of a flagellin-cocaine conjugate vaccine

描述（由申请人提供）：非法药物使用不仅是一个重大的全球健康问题，而且还对社会、政治和经济产生了深刻的负面影响，而且影响的程度还在不断增加。虽然尼古丁贴片或美沙酮等治疗方法在减少吸烟成瘾和鸦片滥用方面很有用，但目前还没有针对可卡因或甲基苯丙胺成瘾的此类治疗方法。鉴于健康问题的严重性和对吸毒成瘾者缺乏适当的药物替代疗法，研究工作的重点是研制防止滥用药物的疫苗的概念。推动这条研究路线的假设很简单——通过抗体结合降低血浆中游离药物的浓度，药物到达大脑的能力就会大大降低，而这种能力足以引发愉悦的强化效应。虽然在研制候选疫苗方面取得了进展，但这些疫苗存在几个严重弱点：诱导抗可卡因抗体滴度不足，需要大量疫苗和大量疫苗接种。我们建议制备可卡因类似物：鞭毛蛋白缀合物，它将利用鞭毛蛋白的强佐剂作用和免疫原性来引发强大的T细胞依赖性抗原特异性抗体反应。根据对基于鞭毛蛋白的疫苗的研究结果，我们完全预期低剂量的疫苗和有限的疫苗接种将诱导滴度至少比以前使用可卡因疫苗获得的滴度高10-50倍。我们将对小鼠和大鼠进行免疫，并评估抗可卡因IgG的血浆滴度，以及免疫和对照动物在给药后的可卡因水平。此外，我们将使用一系列测定方法来评估免疫对这些动物体内可卡因药理作用的影响，以及免疫限制自我给药和依赖发展的可能性。最后，我们将评估非人类灵长类动物免疫对可卡因到达大脑能力的影响。在拟议研究的结论中，我们期望实现以下目标：1)开发一种高效的可卡因类似物：鞭毛蛋白偶联物，可引起强大的抗可卡因IgG反应；2)疫苗介导的可卡因隔离，使进入大脑的最低水平和可卡因的药理作用显着减弱。

DESCRIPTION (provided by applicant): Illicit drug use is not only a major global health problem, but has also had a profoundly negative social, political, and economic impact that continues to increase in magnitude. Although treatments such as the nicotine patch or methadone have been useful in reducing addictions to smoking and opiate abuse, there are currently no such treatments for cocaine or methamphetamine addiction. In view of the magnitude of the health problem and the lack of an appropriate drug substitution therapy for addicts, research efforts have focused on the concept of developing vaccines against drugs of abuse. The hypothesis that drives this line of study is quite simple-by reducing the concentration of free drug in plasma via antibody binding, the ability of the drug to reach the brain in sufficient amounts to elicit a pleasurable, reinforcing effect would be dramatically reduced. Although progress has been made in developing candidate vaccines, these vaccines suffer from several critical weaknesses: insufficient titers of induced anti-cocaine antibodies and the need for large amounts of vaccine and large numbers of vaccinations. We propose to prepare cocaine analog: flagellin conjugates that will take advantage of the potent adjuvant effect and immunogenicity of flagellin to elicit robust T cell- dependent, antigen-specific antibody responses. Based on the results of work on flagellin- based vaccines, we fully expect that low amounts of vaccine and limited vaccinations will induce titers that are at least 10-50x higher than previously obtained with cocaine vaccines. We will immunize mice and rats and evaluate plasma titers of anti-cocaine IgG, as well as the levels of cocaine in immune and control animals following administration of the drug. In addition, we will use a range of assays to assess the effect of immunization on the pharmacological effects of cocaine in these animals, as well as the potential for immunization to limit self-administration and the development of dependence. Finally, we will assess the effect of immunization in nonhuman primates on the ability of cocaine to reach the brain. At the conclusion of the proposed studies, we expect to accomplish the following goals: 1) develop a highly efficacious cocaine analog:flagellin conjugate that elicits a robust anti-cocaine IgG response and 2) vaccine-mediated sequestering of cocaine such that minimal levels enter the brain and the pharmacological effects of cocaine are dramatically muted. PUBLIC HEALTH RELEVANCE: The goal of this project is to develop a vaccine against cocaine that elicits extremely high titers of neutralizing antibodies and that dramatically reduces the reinforcing pleasurable effects of cocaine. If successful, such a vaccine would not only have tremendous potential as a means to reduce cocaine use and addiction in American society, but would also validate the use of flagellin as an adjuvant and vaccine carrier for other drugs of abuse.