Delivery and Adjuvantation of Nicotine Vaccine by Laser Illumination

描述（由申请人提供）：本K99/R00提案寻求高度安全和有效的策略来提高尼古丁疫苗的免疫原性。治疗尼古丁成瘾仍然是一个未满足的医疗需求，尼古丁疫苗通过诱导相对长期的戒断率和较少的副作用，发展成为一种安全有效的治疗尼古丁成瘾的疗法。然而，即使在5-7个月的免疫接种后，也只有一小部分吸烟者对这种疗法有反应。血清抗尼古丁抗体（NicAb）滴度与戒烟率呈正相关，提高尼古丁疫苗的免疫原性仍是提高临床应答率的关键。提出了一种基于烧蚀分数激光（AFL）的颗粒疫苗和佐剂包被透皮贴剂，用于尼古丁疫苗的递送和佐剂。AFL产生可自我再生的微通道（MCs），为疫苗进入皮肤提供免费途径。此外，AFL具有优越的“内置”佐剂作用，通过诱导抗原提呈细胞募集和长期抗原储存，比大多数传统佐剂更有效。将尼古丁疫苗和一种安全的皮肤单磷酰脂质a （MPL）佐剂包封在不同大小的混合聚（D， l -乳酸-羟基乙酸）（PLGA）颗粒中，有望模拟初级/增强免疫，诱导最高和最长的NicAb滴度，并“完全”阻断尼古丁进入大脑。这种新型免疫还有望通过消除针头注射来提高患者的依从性，并诱导早发性和持久的免疫反应。这种新型免疫结合了临床已有的AFL、MPL佐剂和PLGA聚合物，可以深刻提高尼古丁疫苗的免疫原性，如果本研究能够获得足够的安全性和有效性数据，有望获得FDA批准进行临床试验。提出了三个具体目标：1。优化基于afl的贴片疫苗递送，2和3。评估尼古丁疫苗在小鼠(2)和小型猪(3)中的免疫原性。这些目标将通过哈佛-麻省理工学院健康科学系的课程以及与知名科学家的多学科指导和合作来实现。这个应用程序满足了四个主要功能之一

DESCRIPTION (provided by applicant): This K99/R00 proposal seeks highly safe and efficient strategies to improve nicotine vaccine immunogenicity. Treatment of nicotine addiction remains an unmet medical need and nicotine vaccines evolve as a safe and effective therapy to treat nicotine addiction by induction of a relatively long-term abstinence rate with fewer side effects. Yet, only a small fraction of smokers respond to this therapy even after 5-7 monthly immunizations. Enhancing nicotine vaccine immunogenicity remains the key to increase the clinical response rate due to the positive correlation between serum anti-nicotine antibody (NicAb) titer and abstinence rate. An ablative fractional laser (AFL)-based, particulate vaccine and adjuvant-coated transdermal patch is proposed for nicotine vaccine delivery and adjuvantation. The AFL generates self-renewable microchannels (MCs) that provide free paths for vaccine delivery into the skin. Additionally, the AFL possesses superior "built-in" adjuvant effects that are more potent than the majority of traditional adjuvants by induction of antigen presenting cell recruitment and long-term antigen depot. Encapsulation of nicotine vaccine and a safe cutaneous monophosphoryl lipid A (MPL) adjuvant into mixed poly(D,L-lactic-co-glycolic acid) (PLGA) particles with different sizes is expected to simulate a prime/boost immunization and induce the highest and prolonged NicAb titer and "completely" block nicotine entry into the brain. The novel immunization is also expected to improve patient compliance by elimination of needle injection and induce an early-onset and long-lasting immune response. The novel immunization combines AFL, MPL adjuvant, and PLGA polymers already in the clinic to profoundly improve nicotine vaccine immunogenicity and is expected to gain FDA approval for clinical test if sufficient safety and efficacy data can be obtained from this study. Three specifi aims are proposed: 1. Optimize AFL-based patch vaccine delivery, 2 & 3. Evaluate nicotine vaccine immunogenicity in mice (2) and miniature pigs (3). These aims will be achieved through courseworks at Harvard-MIT Division of Health Science and through multidisciplinary mentoring and collaboration with well-established scientists. This application fulfills one of the four major goals "Treatment" and the objective "To develop treatments for drug abuse and addiction in association with comorbid conditions" stated in 2010 NIDA strategic plan, and also addresses broad Challenge Area (15) Translational Science and specific Challenge Topic, 15-DA-101, Novel Approaches to Improve Immunogenicity of Vaccine against Small Molecules. The novel immunization strategy will have a broad impact on delivery and adjuvantation of not only nicotine vaccine, but also other anti- addiction vaccines (e.g., cocaine and heroin vaccines) under development and seasonal influenza vaccines in the clinic. Completion of this project will provide the candidate sufficient experience and a superior technology for transition to an independent researcher career in vaccine delivery and adjuvantation field.