Development of Novel Vaccines for Cocaine Abuse

摘要 可卡因（COC）是一种高度成瘾性和强效中枢神经系统兴奋剂，滥用这种药物可以 导致人类大脑中显著的长期神经认知缺陷。常规药物治疗 临床效果有限。一种替代治疗方法， 帮助预防可卡因滥用复发的有力工具是接种COC疫苗， 在动物和人类研究中的结果。这种疫苗可以引发高浓度的抗体（Ab）， 与可卡因结合，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，药物渴望的特征性增加（药物强化）将减少或 完全抑制。第一次可卡因结合疫苗的人体试验证明可卡因使用减少 在抗体应答良好的受试者中，只有三分之一的免疫受试者达到了充分的阻断， 抗可卡因抗体水平，此外抗体水平在疫苗加强剂量结束后迅速下降。 对可卡因滥用复发的敏感性在戒毒后的几个月内最高， 许多受试者的初始应答和良好应答者的Ab滴度在治疗后数周内迅速下降。 完成加强免疫计划可大大减少这种可卡因疫苗的影响。免疫 免疫应答通常受到严格调节，以允许免疫力的上升和下降， 调节性T细胞（Treg）抑制;因此使用基于Toll样受体（TLR）的小分子调节性T细胞功能。 分子和抗共刺激分子可以显著增强免疫应答。这项建议旨在 通过创新的免疫学研究解决这些关键的疫苗问题，其中包括新型可卡因 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，和生发中心（GC）中B细胞成熟信号的调节， 改善记忆B细胞和长寿浆细胞生成。具体目标是：（1）发展和 将TLR5配体缀合物与可卡因配制用于免疫，以将这些缀合物配制成 将纳米胶囊与其他基于TLR的小分子化合物进行比较，并将反应与标准品进行比较。 载体缀合物疫苗和明矾佐剂，2）为了通过调节COC-特异性抗体应答来改善COC-特异性抗体应答， B细胞活化和生发中心应答，以及3）增强免疫原性和治疗性 可卡因-TLR5配体缀合物和纳米胶囊通过操纵Treg细胞功能的效力。

ABSTRACT 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.