Delivery and Adjuvantation of Nicotine Vaccine by Laser Illumination

激光照明尼古丁疫苗的递送和佐剂

• 批准号: 8999625
• 负责人: Xinyuan Chen
• 金额: $ 24.85万
• 依托单位: UNIVERSITY OF RHODE ISLAND
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-06-15 至 2018-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8999625
• 关键词: APC Vaccine; Abstinence; Address; Adjuvant; Adverse effects; Affinity; Agonist; Antibodies; Antibody Formation; Antigen-Presenting Cells; Antigens; Area; Award; Binding; Blood Circulation; Brain; Cell Maturation; Clinic; Clinical; Cocaine; Collaborations; Cosmetics; Cutaneous; Data; Dendritic Cells; Development; Drug Addiction; Drug Formulations; Drug abuse; Encapsulated; Ensure; Excipients; Family suidae; Foundations; Future; Glycolates; Goals; Health Sciences; Heroin; Human; Human Resources; Immune response; Immunization; Inferior; Injection of therapeutic agent; Intramuscular; Keyhole Limpet Hemocyanin; Langerhans cell; Lasers; Lighting; Lipid A; Medical; Mentors; Modeling; Mus; Muscle; Nanotechnology; National Institute of Drug Abuse; Needles; Nicotine; Nicotine Dependence; Ovalbumin; Painless; Particulate; Pattern; Pharmacology; Phase I Clinical Trials; Placebos; Polymers; Population; Reaction; Reporting; Research Personnel; Safety; Scientist; Serum; Skin; Smoker; Solid; Strategic Planning; Surface; Technology; Time; Tissues; Topical application; Toxic effect; Training; Translational Research; Vaccine Adjuvant; Vaccines; addiction; aluminum sulfate; base; career; clinical efficacy; compliance behavior; early onset; effective therapy; experience; immunogenicity; improved; influenza virus vaccine; intradermal injection; multidisciplinary; nanoparticle; novel; novel strategies; particle; pre-clinical; research clinical testing; response; restoration; seasonal influenza; small molecule; toll-like receptor 4; vaccine delivery

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.

该 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。 尼古丁成瘾的治疗仍然是一个未满足的医疗需求，尼古丁疫苗已发展成为一种安全且可靠的方法。 通过较少的副作用诱导相对长期的戒烟率来治疗尼古丁成瘾的有效疗法 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。 增强尼古丁疫苗的免疫原性仍然是提高临床缓解率的关键 血清抗尼古丁抗体（NicAb）滴度与戒烟率呈正相关。夺格 提议使用基于点阵激光 (AFL) 的颗粒疫苗和佐剂涂层透皮贴剂 尼古丁疫苗的递送和佐剂。 AFL 生成可自我更新的微通道 (MC) 为疫苗输送到皮肤提供自由路径。此外，AFL 还拥有卓越的“内置”佐剂 通过诱导抗原呈递细胞产生比大多数传统佐剂更有效的效果 招募和长期抗原库。尼古丁疫苗的封装和安全的皮肤 将单磷酰脂质 A (MPL) 佐剂加入混合聚 (D,L-乳酸-乙醇酸) (PLGA) 颗粒中 不同尺寸预计可模拟初免/加强免疫并诱导最高和延长的 NicAb 滴度并“完全”阻止尼古丁进入大脑。新型免疫也有望改善 通过消除针头注射来提高患者的依从性，并诱导早发和持久的免疫 回复。这种新型免疫结合了 AFL、MPL 佐剂和已在临床使用的 PLGA 聚合物， 深刻提高尼古丁疫苗免疫原性，有望获得FDA批准进行临床试验 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 和 3。评估小鼠中的尼古丁疫苗免疫原性 (2) 和 小型猪 (3).这些目标将通过哈佛-麻省理工学院健康部的课程来实现 科学以及通过多学科指导以及与知名科学家的合作。这 申请实现了四个主要目标之一“治疗”和目标“开发药物治疗方法” 2010 年 NIDA 战略计划中指出，“与共病相关的滥用和成瘾”，以及 解决广泛的挑战领域 (15) 转化科学和具体挑战主题，15-DA-101，小说 提高小分子疫苗免疫原性的方法。新型免疫策略 不仅会对尼古丁疫苗的交付和佐剂产生广泛的影响，而且还会对其他抗尼古丁疫苗的交付和佐剂产生广泛的影响。 正在开发的成瘾疫苗（例如可卡因和海洛因疫苗）和季节性流感疫苗 诊所。完成该项目将为候选人提供足够的经验和卓越的技术 过渡到疫苗输送和佐剂领域的独立研究人员职业。