Development of Novel Vaccines for Cocaine Abuse

描述（由申请人提供）：可卡因（COC）是一种高度成瘾的强效中枢神经系统兴奋剂，滥用该药物可导致人类大脑中严重的长期神经认知缺陷。COC滥用的常规药物治疗具有有限的临床有效性。另一种可能成为帮助预防可卡因滥用复发的有力工具的治疗方法是接种COC疫苗，该疫苗在动物和人体研究中都显示出有希望的结果。这种疫苗可以引发高浓度的抗体（Abs），这些抗体结合可卡因，将其保留在循环中，并抑制其进入大脑。理想情况下，当接种疫苗的个体可能使用药物时，药物渴望的特征性增加（药物强化）将被减少或完全抑制。第一次可卡因偶联疫苗人体试验表明，在抗体应答良好的受试者中可卡因使用减少，但只有三分之一的免疫受试者达到了足够的抗可卡因抗体阻断水平，而且在疫苗加强剂量结束后，抗体水平迅速下降。可卡因滥用复发的易感性在停药后的几个月内最高，因此许多受试者的初始应答较低，以及在完成加强方案后数周内良好应答者的Ab滴度快速下降，可能会大大降低这种可卡因疫苗的影响。免疫反应通常受到严格调节，以允许免疫力的上升和下降，并通过调节性T细胞（Treg）抑制介导免疫力的下降;因此，使用基于Toll样受体（TLR）的小分子和抗共刺激分子调节Treg功能可以显着增强免疫反应。该提案试图通过创新的免疫学研究来解决这些关键的疫苗问题，这些研究将包括新的可卡因缀合物构建、纳米胶囊疫苗制剂、辅助信号刺激、阻断Treg应答的诱导以及在生发中心（GC）中调节B细胞成熟信号以改善记忆B细胞和长寿浆细胞的产生。具体目的是1）开发和配制用于免疫的具有可卡因的TLR 5配体缀合物，将这些缀合物与其它基于TLR的小分子化合物一起配制成纳米胶囊，并与标准载体缀合物疫苗和明矾佐剂比较应答，2）通过调节B细胞活化和生发中心应答来改善COC特异性抗体应答，和3）通过操纵Treg细胞功能来增强可卡因-TLR 5配体缀合物和纳米胶囊的免疫原性和治疗效力。 公共卫生相关性：可卡因滥用/依赖在世界各地都有深刻的社会和经济影响，长期使用可导致成瘾者个人出现严重的神经心理缺陷。帮助治疗这种成瘾的一种特别有吸引力的替代方法是针对该药物的疫苗接种，这种治疗可以成为通过阻断其药理作用来预防这种物质滥用复发的有力工具。这项研究将集中在新的缀合物疫苗构建体，纳米胶囊疫苗制剂和新的方法，以提高高浓度抗可卡因抗体反应的幅度和持久性，可以抑制可卡因进入大脑。

DESCRIPTION (provided by applicant): Cocaine (COC) is a highly addictive and a potent central nervous system stimulant, and abuse of this drug can result in significant long-term neurocognitive deficits in the human brain. Conventional pharmacotherapies for COC abuse have had limited clinical effectiveness. An alternative treatment approach that could become a powerful tool to help prevent cocaine abuse relapse, is vaccination against COC, which has shown promising results in both animal and human studies. Such vaccines can elicit high concentrations of antibodies (Abs) that bind cocaine, retain it in the circulation, and inhibit its entry into the brain. Ideally, when a vaccinated individual might use the drug, the characteristic increase in drug cravings (drug reinforcement) will be diminished or completely inhibited. The first human trial with cocaine conjugate vaccines demonstrated reduced cocaine use in subjects who had good Ab responses, but only a third of immunized subjects achieved adequate blocking levels of anti-cocaine Abs, and furthermore Ab levels declined rapidly after the vaccine booster doses ended. Susceptibility to cocaine abuse relapse is highest for several months after withdrawal from the drug, and so low initial responses in many subjects and a rapid decline of the Ab titers in good responders within weeks after completion of the booster schedule could substantially reduce the impact of this cocaine vaccine. Immune responses are ordinarily tightly regulated to permit a rise and fall of immunity with the decline mediated by regulatory T cell (Treg) suppression; so modulating Treg function using toll like receptor (TLR)-based small molecules and anti-costimulatory molecules can markedly enhance immune responses. This proposal seeks to address these critical vaccine problems by innovative immunological studies, which will include novel cocaine conjugate construction, nanocapsules vaccine formulations, accessory signal stimulation, blocking the induction of Treg responses, and modulation of B cell maturation signals in the germinal centers (GCs) to improve memory B-cell and long-lived plasma cell generation. The specific aims are 1) To develop and formulate TLR5 ligand conjugates with cocaine for immunizations, to formulate these conjugates into nanocapsules with other TLR-based small molecule compounds, and to compare responses with standard carrier conjugate vaccines and alum adjuvant, 2) To improve COC-specific antibody responses by modulating B cell activation and germinal center responses, and 3) To enhance the immunogenicity and therapeutic potency of cocaine-TLR5 ligand conjugates and nanocapsules by manipulating Treg cell function. PUBLIC HEALTH RELEVANCE: Cocaine abuse/dependence has profound social and economic effects in all parts of the world, and chronic use can lead to significant neuropsychological defects in individual addicts. An especially attractive alternative approach to help treat this addiction is vaccination against the drug, a treatment that could become a powerful tool in preventing relapse to abuse of this substance by blocking its pharmacological effects. This research will focus on novel conjugate vaccine constructs, nanocapsules vaccine formulations, and new methods to enhance the magnitude and persistence of high concentration anti-cocaine antibody responses that can inhibit the entry of cocaine into the brain.