Biomaterial Strategies for Modulating the Immune Response

调节免疫反应的生物材料策略

• 批准号: 10232052
• 负责人: Kevin James McHugh
• 金额: $ 10.67万
• 依托单位: RICE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-08-10 至 2022-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10232052
• 关键词: 3D Print; Address; Adjuvant; Aluminum Hydroxide; Anatomy; Antibodies; Antibody Formation; Antigens; Area; B-Lymphocytes; Biocompatible Materials; Biological Phenomena; Cause of Death; Cessation of life; Chemistry; Child; Clinical; Communicable Diseases; Complex; Dendritic Cells; Dermis; Development; Devices; Disease; Dose; Dropout; Drops; Economics; Elements; Emulsions; Engineering; Environment; Environmental Risk Factor; Evaluation; Exhibits; Exposure to; Formulation; Glycolates; Health Care Costs; High Prevalence; Human Papillomavirus; Hydration status; Hydrogels; Immune response; Immunity; Immunization; Immunization Schedule; In Situ; Individual; Infant; Injections; Kinetics; Logistics; Malaria Vaccines; Malignant neoplasm of cervix uteri; Mechanics; Mediating; Meningitis; Methods; Molecular Conformation; Nature; Physiologic pulse; Polymers; Procedures; Process; Property; Regimen; Research; Resolution; Resources; Risk; Self Administration; Shapes; Site; Skin; Solvents; Structure; Subunit Vaccines; Surface; Technology; Time; United States; Vaccination; Vaccines; Work; World Health Organization; base; clinically relevant; controlled release; cost; density; evaporation; immunogenic; immunogenicity; immunomodulatory strategy; improved; in vivo; lymph nodes; nanoparticle; neutralizing antibody; novel; pain reduction; particle; polymerization; preclinical study; prevent; programs; residence; seroconversion; success; tool; two-photon; vaccine delivery; vaccine development; vaccine distribution; vaccine response; vaccine trial

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.

项目概要/摘要 尽管世界卫生组织的扩大免疫规划取得了巨大成功， 过去 44 年里，传染病拯救了数百万人的生命，但它仍然是第二大原因 全球死亡人数。1-4 每年发生的 1500 万人死亡中，10% 是可以通过疫苗预防的，但仍在继续 由于在整个过程中进行多次注射相关的后勤挑战而发生 5 剩余 90% 的死亡无法通过现有疫苗和疫苗来预防 可能需要开发针对关键疾病目标的高免疫原性疫苗。6,7 例如， RTS,S/AS01 (MosquirixTM) 是唯一获得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 尽管额外剂量可能会进一步改善血清转化 率，对额外剂量的经济和社会耐受性是有限的。 9 相反，增强剂量的策略 抗原免疫原性可能能够：（1）在较少剂量后达到相似水平的血清转化，（2） 提高相同剂量接种后的血清转化率，和/或 (3) 允许使用亚单位疫苗 通常更安全、更稳定，但本质上免疫原性较低。 10 除了解决明确的问题 发展中国家的临床需求，该策略也适用于发达国家，特别是人类 乳头瘤病毒 (HPV) 和脑膜炎疫苗，需要多次接种，但初始接种率较低 依从性（美国的一剂覆盖率分别为 66% 和 85%）和高退出率（25% 和 接受一剂疫苗的人中有 52% 没有接受第二剂）。11-13 我的博士后研究主要是 专注于开发使用可生物降解微粒的单次注射疫苗接种平台 以模拟多次注射的离散脉冲释放抗原该提议建立在我之前的工作的基础上。 其目的不仅是复制多次注射免疫方案的免疫原性，而且还增强疫苗 使用三种定时或靶向疫苗递送策略的免疫原性。 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 表现出良好控制的释放动力学并保护抗原免受有害环境因素的影响。 最佳疫苗释放动力学尚未确定，14这些设备还将用于确定 第二种方法将为皮内制造可溶解的微针贴片。 通过利用皮肤和细胞中高浓度的树突状细胞来输送控释疫苗。 由于延迟释放的好处，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、减少疼痛以及自我给药的潜力。 该提案中提出的第三个策略将探索使用原位形成水凝胶，该水凝胶可在 淋巴结并随着时间的推移释放疫苗，以延长抗原停留时间和与初始 B 细胞的接触。