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: 9088422
• 负责人: Xinyuan Chen
• 金额: $ 24.53万
• 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/9088422
• 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 abuse; Encapsulated; Ensure; Excipients; Family suidae; Formulation; 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; 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; TLR4 gene; 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; mouse model; multidisciplinary; nanoparticle; novel; novel strategies; particle; pre-clinical; research clinical testing; response; restoration; seasonal influenza; small molecule; 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.

这项K99/R00提案寻求高度安全和高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得到满足的医疗需求，尼古丁疫苗作为一种安全和 通过较少副作用诱导相对长期的戒断率来治疗尼古丁成瘾的有效疗法 效果。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。 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，因为 血清抗尼古丁抗体效价与戒断率呈正相关。一种烧蚀剂 提出了基于分数激光(AFL)的颗粒疫苗和佐剂包衣透皮贴剂用于 尼古丁疫苗的投放和辅助治疗。AFL产生可自我更新的微通道(MC) 为疫苗进入皮肤提供免费途径。此外，AFL还拥有卓越的“内置”佐剂 通过诱导抗原提呈细胞产生比大多数传统佐剂更有效的效果 招募和长期的抗原库。尼古丁疫苗的包装及安全皮肤 单磷脂A佐剂与聚(D，L-乳酸-羟基乙酸)共混微球 不同的大小有望模拟初始/增强免疫，并诱导最高和持续时间最长的NicAb 滴度和“完全”阻止尼古丁进入大脑。新的免疫接种也有望得到改善 通过消除针头注射和诱导早期起病和持久的免疫来实现患者的依从性 回应。新型免疫结合了AFL、MPL佐剂和已在临床上使用的PLGA聚合物，以 大大提高尼古丁疫苗的免疫原性，并有望获得FDA的临床测试批准，如果 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的补丁疫苗递送，2和3。评估尼古丁疫苗在小鼠中的免疫原性(2)和 小型猪(3头)。这些目标将通过哈佛-麻省理工学院健康部门的课程来实现 科学和多学科指导以及与知名科学家的合作。这 应用实现了四大目标之一--“治疗”和“发展药物治疗 2010年NIDA战略计划中所述的“与共病有关的滥用和上瘾”，以及 解决广泛的挑战领域(15)翻译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途径。新的免疫策略 不仅会对尼古丁疫苗的投放和佐剂产生广泛影响，而且还会对其他抗病毒药物产生影响 正在开发的成瘾疫苗(例如可卡因和海洛因疫苗)和#年的季节性流感疫苗 诊所。该项目的完成将为应聘者提供足够的经验和优越的技术 过渡到疫苗输送和佐剂领域的独立研究人员职业生涯。