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.

项目摘要/摘要 尽管世界卫生组织扩大的免疫计划取得了巨大成功，但 在过去的44年中，它挽救了数百万人的生命，传染病仍然是第二个主要原因 全世界死亡的死亡。每年发生的1500万死亡中的1-4个，有10％是可预防疫苗的，但继续 由于与在整个过程中进行多次注射有关的后勤挑战而发生的 低资源环境中的月份。5现有疫苗无法预防其余90％的死亡 可能需要开发针对关键疾病靶标的高度免疫原性疫苗。例如，6,7 RTS，S/AS01（MosquirixTM），唯一的临床批准疟疾疫苗，仅在仅26％的幼儿中有效 3剂和39％的儿童4剂量后。8虽然额外的剂量可能会进一步改善血清转化 费率，经济和社会宽容有限 抗原免疫原性可能能够：（1）剂量较少后达到相似水平的血清转化水平，（2） 在相同剂量数量后提高血清转化率，/或（3）启用亚基疫苗 通常更安全，更稳定，但固有的免疫原性。10除了解决一个清晰的问题之外 发展中国家的临床需求，该策略也与发达国家有关，尤其是人类 乳头瘤病毒（HPV）和脑膜炎疫苗，需要多种剂量，但初始初始剂量较低 合规性（美国分别为66％和85％的一剂量覆盖率）和高辍学率（25％和25％ 52％接受一剂的人没有获得一秒钟）.11-13我的博士后研究有主要 专注于使用可生物降解的微粒进行的单注射疫苗接种平台的开发 在模仿多重注射的离散脉冲中释放抗原。这项建议是基于我以前的工作 并旨在不仅复制多注射免疫抑制方案的免疫原性，还可以增强疫苗 使用三种定时或靶向疫苗输送策略的免疫原性。第一种方法将发展 使用超高分辨率3D打印来制造表面擦拭微粒的疫苗输送平台 暴露了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。因为 最佳疫苗释放动力学尚未确定，14这些设备也将用于确定 有利的发行轮廓。第二种方法将为皮内创建可溶解的微针斑块 输送受控释放疫苗。通过利用皮肤中高浓度的树突状细胞和 延迟释放的好处，这些配方可能能够增强疫苗免疫原性 其他优势，例如改善的抗原稳定性，减轻疼痛以及自我管理的潜力。 本提案中提出的第三个策略将探讨自我组装的原位形成水凝胶的使用 随着时间的流逝，淋巴结并释放疫苗，以延长抗原停留时间和暴露于幼稚的B细胞。