Development of Novel Vaccines for Cocaine Abuse

描述（由申请人提供）：可卡因（COC）是一种高度成瘾性和强效中枢神经系统兴奋剂，滥用这种药物会导致人类大脑严重的长期神经认知缺陷。常规药物治疗COC滥用的临床效果有限。另一种可能成为帮助防止可卡因滥用复发的有力工具的治疗方法是针对COC的疫苗接种，该方法在动物和人体研究中都显示出令人鼓舞的结果。这种疫苗可以引起高浓度的抗体（Abs），这种抗体可以结合可卡因，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（药物强化）的特征增加将减少或完全抑制。可卡因结合疫苗的首次人体试验表明，具有良好抗体反应的受试者减少了可卡因的使用，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。在停药后的几个月内，可卡因滥用复发的易感性最高，因此，许多受试者的初始反应较低，而在完成加强计划后的几周内，良好应答者的Ab滴度迅速下降，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，允许免疫的上升和下降，并由调节性T细胞（Treg）抑制介导的下降；因此，利用toll样受体（TLR）小分子和抗共刺激分子调节Treg功能可显著增强免疫应答。该提案旨在通过创新的免疫学研究来解决这些关键的疫苗问题，其中包括新的可卡因偶联物构建，纳米胶囊疫苗配方，辅助信号刺激，阻断Treg反应的诱导，以及在生发中心（GCs）调节B细胞成熟信号，以改善记忆B细胞和长寿命浆细胞的产生。具体目的是：1)开发和制备用于免疫的TLR5配体与可卡因偶联物，将这些偶联物与其他tlr基小分子化合物制成纳米胶囊，并与标准载体偶联疫苗和明本佐剂比较反应；2)通过调节B细胞活化和生发中心反应来改善coc特异性抗体反应。3)通过调控Treg细胞功能，增强可卡因- tlr5配体缀合物和纳米胶囊的免疫原性和治疗效力。

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.