Delivery and Adjuvantation of Nicotine Vaccine by Laser Illumination

描述(由申请人提供)：这项K99/R00提案寻求高度安全和有效的策略，以提高尼古丁疫苗的免疫原性。尼古丁成瘾的治疗仍然是一个未得到满足的医学需求，尼古丁疫苗通过诱导相对长期的戒断率和较少的副作用而成为一种安全有效的治疗尼古丁成瘾的方法。然而，即使在每月接种5-7次疫苗后，也只有一小部分吸烟者对这种疗法有反应。由于血清抗尼古丁抗体效价与戒断率呈正相关，提高尼古丁疫苗的免疫原性仍是提高临床应答率的关键。提出了一种基于消融分数激光(AFL)的微粒疫苗和佐剂包衣透皮贴片，用于尼古丁疫苗的递送和佐剂治疗。AFL产生自我更新的微通道(MC)，为疫苗进入皮肤提供自由路径。此外，AFL具有优越的“内置”佐剂效果，通过诱导抗原呈递细胞募集和长期抗原库，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脂A佐剂包裹到不同大小的混合聚(D，L-乳酸-乙醇酸)(PLGA)颗粒中，有望模拟初始/增强免疫，诱导最高和持续时间最高的尼古丁抗体效价，并“完全”阻止尼古丁进入大脑。这种新型免疫还有望通过消除针头注射来改善患者的依从性，并诱导起病早和持久的免疫反应。这种新型免疫结合了AFL、MPL佐剂和PLGA聚合物，极大地提高了尼古丁疫苗的免疫原性，如果从这项研究中获得足够的安全性和有效性数据，有望获得FDA的临床试验批准。提出了三个具体的目标：1.优化AFL补丁疫苗的接种，2&3.评价尼古丁疫苗在小鼠(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部的课程工作以及通过多学科指导和与知名科学家的合作来实现。此应用程序实现了四个主要功能之一 目标“治疗”和2010年NIDA战略计划中所述的“开发药物滥用和成瘾的治疗方法”的目标，还涉及广泛的挑战领域(15)转化科学和具体挑战专题，15-DA-101，提高小分子疫苗免疫原性的新方法。新的免疫策略不仅将对尼古丁疫苗的提供和佐剂产生广泛影响，还将对正在开发的其他抗成瘾疫苗(例如可卡因和海洛因疫苗)和诊所的季节性流感疫苗的交付和佐剂产生广泛影响。该项目的完成将为候选人提供足够的经验和优越的技术，以过渡到疫苗输送和佐剂领域的独立研究人员生涯。

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.