Biomaterial Strategies for Modulating the Immune Response

项目摘要/摘要 尽管世界卫生组织扩大的免疫接种计划取得了巨大成功， 在过去的44年里，传染病拯救了数百万人的生命，它仍然是第二大原因 1-每年发生的1500万例死亡中，有10%是可以通过疫苗预防的，但仍在继续 发生的原因是与在整个过程中进行多次注射相关的后勤挑战 5其余90%的死亡不能用现有的疫苗和 可能需要开发针对关键疾病目标的高度免疫原性疫苗。 S/AS01(MosquirixTM)是唯一一种临床批准的疟疾疫苗，仅对26%的幼儿有效 3剂后，39%的儿童在4剂后。8尽管额外的剂量可能会进一步提高血清转化率 但是，经济和社会对额外剂量的容忍是有限度的。9相反，加强 抗原免疫原性可能能够：(1)在较少的剂量下达到类似水平的血清转换，(2) 提高相同剂量后的血清转换率，和/或(3)能够使用亚单位疫苗 通常更安全和更稳定，但固有的免疫原性较低。10除了解决明确的 发展中国家的临床需求，这一战略也适用于发达国家，特别是对人类。 乳头瘤病毒(HPV)和脑膜炎疫苗，需要多次接种，但初始剂量较低 合规性(美国的单剂覆盖率分别为66%和85%)和高辍学率(25%和 接受一剂疫苗的人中有52%没有接受第二剂疫苗)。11-13我的博士后研究主要是 重点开发了一次注射疫苗平台，使用可生物降解的微粒来 在模拟多次注射的离散脉冲中释放抗原。这项建议是在我以前工作的基础上提出的 其目的不仅是复制多次注射免疫方案的免疫原性，而且要增强疫苗 使用三种定时或靶向疫苗投放策略的免疫原性。第一种方法将开发一种 一种使用超高分辨率3D打印制造表面侵蚀微粒的疫苗输送平台 表现出良好的控制释放动力学，并保护抗原免受有害环境因素的影响。因为 最佳疫苗释放动力学尚未确定，14这些装置也将用于确定 有利的释放配置文件。第二种方法将为真皮内创建可溶解的微针贴片 提供受控释放疫苗。通过利用皮肤和皮肤中高浓度的树突状细胞 延迟释放的好处，这些制剂可能能够增强疫苗的免疫原性，同时提供 其他优点，如提高抗原稳定性，减轻疼痛，以及自我给药的潜力。这个 本提案中提出的第三个战略将探索使用原位形成的水凝胶，这些水凝胶在 随着时间的推移，淋巴和释放疫苗可以延长抗原的滞留时间和暴露在幼稚的B细胞中。

PROJECT SUMMARY/ABSTRACT Despite the enormous success of the World Health Organization's Expanded Programme on Immunization, which has saved millions of lives over the past 44 years, infectious disease remains the second leading cause of death worldwide.1-4 Of the 15 million deaths that occur each year, 10% are vaccine-preventable, yet continue to occur due to the logistical challenges associated with administering multiple injections over the course of months in low-resource settings.5 The remaining 90% of deaths cannot be prevented with existing vaccines and will likely require the development of highly immunogenic vaccines against key disease targets.6,7 For example, RTS,S/AS01 (MosquirixTM), the only clinically-approved malaria vaccine, is effective in just 26% of young children after 3 doses and 39% of children after 4 doses.8 Although additional doses may further improve seroconversion rates, there are limits to economic and societal tolerance for additional doses.9 Instead, strategies that enhance antigen immunogenicity may be able to: (1) achieve similar levels of seroconversion after fewer doses, (2) improve seroconversion rates after the same number of doses, and/or (3) enable the use of subunit vaccines that are typically safer and more stable, but inherently less immunogenic.10 In addition to addressing a clear clinical need in the developing world, this strategy is also relevant for the developed world, especially for human papillomavirus (HPV) and meningitis vaccines, which require multiple doses, but are subject to low initial compliance (one-dose coverage of 66% and 85% in the U.S., respectively) and high drop-out rates (25% and 52% of individuals that receive one dose do not receive a second).11-13 My postdoctoral research has primarily focused on the development of a single-injection vaccination platform that uses biodegradable microparticles to release antigen in discrete pulses that mimic multiple injections. This proposal builds off of my previous work and aims to not just replicate the immunogenicity of multi-injection immunization regimens, but enhance vaccine immunogenicity using three timed or targeted vaccine delivery strategies. The first approach will develop a vaccine delivery platform that uses ultrahigh resolution 3D printing to fabricate surface-eroding microparticles that exhibit well-controlled release kinetics and protect antigen from harmful environmental factor. Because optimal vaccine release kinetics have yet to not been identified,14 these devices will also be used to determine favorable release profiles. The second approach will create dissolvable microneedle patches for the intradermal delivery of controlled release vaccines. By leveraging the high concentration of dendritic cells in the skin and benefits of delayed release, these formulations may be able to enhance vaccine immunogenicity while offering other advantages such as improved antigen stability, reduced pain, and the potential for self-administration. The third strategy presented in this proposal will explore the use of in situ-forming hydrogels that self-assemble in the lymph node and release vaccine over time to prolong antigen residence time and exposure to naïve B cells.