Development of a flagellin-cocaine conjugate vaccine

描述(申请人提供)：非法药物使用不仅是一个主要的全球健康问题，而且还产生了严重的负面社会、政治和经济影响，而且影响的幅度还在继续增加。尽管尼古丁贴片或美沙酮等疗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治疗方法。鉴于健康问题的严重性，以及缺乏针对成瘾者的适当的药物替代疗法，研究工作的重点是开发针对滥用药物的疫苗的概念。推动这一研究路线的假设非常简单--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将大大降低，从而产生令人愉悦的强化效果。尽管在开发候选疫苗方面取得了进展，但这些疫苗存在几个严重的弱点：诱导的抗可卡因抗体效价不足，以及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：鞭毛蛋白结合物，它将利用鞭毛蛋白强大的佐剂作用和免疫原性来诱导强大的T细胞依赖性、抗原特异性抗体反应。根据鞭毛蛋白疫苗的工作结果，我们完全预计，低剂量疫苗和有限的疫苗接种将导致效价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，并评估抗可卡因抗体的血浆效价，以及在给药后免疫动物和对照动物中的可卡因水平。此外，我们将使用一系列检测方法来评估免疫对可卡因在这些动物体内的药理作用的影响，以及免疫接种限制自我管理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的能力的影响。在拟议的研究结束时，我们希望实现以下目标：1)开发一种高效的可卡因类似物：鞭毛蛋白结合物，可引起强大的抗可卡因免疫球蛋白反应；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著减弱。 与公共卫生相关：该项目的目标是开发一种针对可卡因的疫苗，该疫苗能引起极高滴度的中和抗体，并极大地减少可卡因增强的愉悦效果。如果成功，这样的疫苗不仅将作为一种手段在美国社会减少可卡因的使用和成瘾，而且还将验证鞭毛蛋白作为其他滥用药物的佐剂和疫苗载体的使用。

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.