Delivery and Adjuvantation of Nicotine Vaccine by Laser Illumination

该K99/R 00提案寻求高度安全和有效的策略来改善尼古丁疫苗的免疫原性。 尼古丁成瘾的治疗仍然是一个未满足的医疗需求，尼古丁疫苗作为一种安全和有效的治疗方法， 通过诱导相对长期戒断率和较少副作用来治疗尼古丁成瘾的有效疗法 方面的影响.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。 提高尼古丁疫苗的免疫原性仍然是提高临床应答率的关键， 血清抗尼古丁抗体（NicAb）滴度与戒烟率呈正相关。消融 提出了一种基于分数激光（AFL）的颗粒疫苗和清除剂涂层透皮贴剂， 尼古丁疫苗递送和佐剂。AFL产生自再生微通道（MC）， 为疫苗进入皮肤提供自由通道。此外，AFL具有上级的“内置”佐剂， 通过诱导抗原呈递细胞， 募集和长期抗原库。尼古丁疫苗的微胶囊化及其安全的皮肤用 将单磷酰脂质A（MPL）佐剂加入混合的聚（D，L-乳酸-共-乙醇酸）（PLGA）颗粒中， 预期不同大小模拟初免/加强免疫并诱导最高和延长的NicAb 滴度和“完全”阻止尼古丁进入大脑。新的免疫也有望改善 通过消除针头注射和诱导早发性和持久的免疫， 反应新的免疫结合AFL，MPL佐剂，和PLGA聚合物已经在临床上， 显著提高尼古丁疫苗免疫原性，并有望获得FDA批准用于临床试验， 从这项研究中可以获得足够的安全性和有效性数据。提出了三个具体目标：1。 优化基于AFL的贴片疫苗递送，2 & 3.评价小鼠中尼古丁疫苗的免疫原性（2）， 小型猪（3）这些目标将通过哈佛-麻省理工学院卫生部的课程来实现 科学和通过多学科的指导和合作，与著名的科学家。这 应用实现了四大目标之一“治疗”和目标“开发药物治疗”， 2010年NIDA战略计划中指出的“与合并症相关的滥用和成瘾”， 解决广泛的挑战领域（15）转化科学和特定的挑战主题，15-DA-101，小说 提高小分子疫苗免疫原性的途径。新的免疫策略 将不仅对尼古丁疫苗，而且对其他抗- 成瘾疫苗（例如，可卡因和海洛因疫苗）和 诊所该项目的完成将为候选人提供足够的经验和上级技术 过渡到疫苗输送和佐剂领域的独立研究人员职业生涯。

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 specific 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.