Development of Novel Vaccines for Cocaine Abuse

摘要 可卡因(COC)是一种高度成瘾和强大的中枢神经系统刺激剂，滥用这种药物可以 会导致人类大脑中严重的长期神经认知缺陷。传统药物疗法 对于COC滥用的临床效果有限。一种替代治疗方法，可能成为 帮助防止可卡因滥用复发的有力工具是针对COC的疫苗接种，这已显示出前景光明 在动物和人类研究中都有结果。这样的疫苗可以诱导高浓度的抗体(Abs)， 结合可卡因，将其留在循环中，并阻止其进入大脑。理想情况下，当一个接种疫苗的人 可能使用药物，药物渴求的特征增加(药物强化)将会减少或 完全被禁止。首次使用可卡因结合疫苗进行的人体试验显示可卡因使用量减少。 在抗体反应良好的受试者中，但只有三分之一的免疫受试者实现了充分的阻断 在疫苗加强剂量结束后，抗可卡因抗体水平以及抗体水平迅速下降。 在戒毒后的几个月里，可卡因滥用复发的易感性最高，因此很低 许多受试者的初始反应和良好应答者的抗体效价在几周内迅速下降 完成加强免疫计划可以大大减少这种可卡因疫苗的影响。免疫 反应通常受到严格的调控，以允许免疫力的起伏，而免疫力的下降是由 调节性T细胞(Treg)抑制；基于Toll样受体(TLR)的Small调节Treg功能 分子和抗共刺激分子能显著增强免疫反应。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，其中将包括新型可卡因 结合物结构，纳米胶囊疫苗制剂，辅助信号刺激，阻断 Treg反应的诱导，以及生发中心(GC)中B细胞成熟信号的调制 改善记忆B细胞和长寿浆细胞的生成。具体目标是：1)发展和发展 将TLR5配体与可卡因制成免疫结合物，将这些结合物制成 纳米胶囊与其他基于TLR的小分子化合物的比较，并与标准响应进行比较 载体结合疫苗和明胶佐剂，2)通过调节提高COC特异性抗体应答 B细胞活化和生发中心反应；3)增强免疫原性和治疗性 可卡因-TLR5配体结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.