Development of Novel Vaccines for Cocaine Abuse

描述(申请人提供)：可卡因(COC)是一种高度上瘾和强大的中枢神经系统刺激剂，滥用该药物可导致人类大脑严重的长期神经认知缺陷。针对COC滥用的传统药物疗法的临床疗效有限。另一种可能成为帮助防止可卡因滥用复发的有力工具的替代治疗方法是针对COC的疫苗接种，这在动物和人体研究中都显示出了令人振奋的结果。这种疫苗可以诱导高浓度的抗体(Abs)与可卡因结合，将其保留在循环中，并阻止其进入大脑。理想情况下，当接种疫苗的个体可能使用该药物时，药物渴望的特征增加(药物强化)将被减少或完全抑制。第一次使用可卡因结合疫苗进行的人体试验表明，抗体反应良好的受试者可卡因使用量减少，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。在停药后的几个月内，可卡因滥用复发的易感性是最高的，因此许多受试者的低初始反应以及良好应答者在完成加强免疫计划后的几周内抗体效价迅速下降，可以大大降低这种可卡因疫苗的影响。免疫反应通常受到严格的调控，以允许免疫的起伏，而调节性T细胞(Treg)抑制介导的免疫下降；因此，使用基于Toll样受体(Toll Like Receptor，TLR)的小分子和抗共刺激分子来调节Treg的功能可以显著增强免疫反应。这项建议旨在通过创新的免疫学研究来解决这些关键的疫苗问题，包括新型可卡因结合物结构、纳米胶囊疫苗配方、辅助信号刺激、阻断Treg反应的诱导，以及调节生发中心(GC)的B细胞成熟信号以改善记忆B细胞和长寿浆细胞的生成。其具体目标是：1)开发和制备TLR5与可卡因的配体结合物用于免疫，将这些结合物与其他基于TLR的小分子化合物制成纳米胶囊，并与标准载体结合疫苗和明胶佐剂进行比较；2)通过调节B细胞的激活和生发中心的反应来提高COC特异性抗体的应答；3)通过调节Treg细胞的功能来增强可卡因-TLR5配体结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/依赖在世界各地具有深远的社会和经济影响，长期使用可卡因可导致个别吸毒者严重的神经心理缺陷。帮助治疗这种成瘾的一个特别有吸引力的替代方法是针对这种药物的疫苗接种，这种治疗方法可能会成为一种强大的工具，通过阻断其药理作用来防止这种物质再次滥用。这项研究将集中在新的结合疫苗结构，纳米胶囊疫苗配方，以及提高高浓度抗可卡因抗体反应的幅度和持久性的新方法，这些抗体反应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.