Electrosprayed Core-Shell Microparticles as a Pulsatile Vaccine Delivery Platform

电喷雾核壳微粒作为脉冲疫苗输送平台

• 批准号: 10195135
• 负责人: Kevin James McHugh
• 金额: $ 7.29万
• 依托单位: RICE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-03-15 至 2022-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10195135
• 关键词: Aerosols; Affect; Antigens; Back; Blood group antigen S; Child; Childhood; Communicable Diseases; Communities; Development; Dextrans; Dose; Drug Delivery Systems; Dyes; Encapsulated; Ensure; Environment; Exhibits; Formulation; Glycolates; Immune system; Immunity; Immunization; In Vitro; Injectable; Injections; Kinetics; Label; Life Cycle Stages; Location; Measures; Methods; Modeling; Molecular Conformation; Monitor; Mus; Needles; Nucleosome Core Particle; Organic solvent product; Particle Size; Patients; Pharmaceutical Preparations; Phosphate Buffer; Physiologic pulse; Polymers; Population; Process; Production; Property; Protein Conformation; Proteins; Regimen; Reporter; Resources; Risk; Rural Community; Saline; Series; Solvents; Structure; Subcutaneous Injections; System; Temperature; Testing; Thick; Time; Travel; Uninsured; Vaccination; Vaccines; World Health Organization; aqueous; biodegradable polymer; clinical translation; controlled release; cost; crystallinity; density; fight against; fluorescence imaging; health care availability; in vivo; low and middle-income countries; macromolecule; negative affect; neutralizing antibody; particle; pathogen; prevent; preventable death; programs; success; tool; vaccination outcome; vaccination schedule; vaccine delivery; vaccine development; vaccine distribution; voltage

PROJECT SUMMARY/ABSTRACT Every year an estimated 19.4 million children do not receive the set of vaccines recommended by the World Health Organization, leading to 1.5 million vaccine-preventable deaths.1,2 A majority of undervaccinated children live in low- and middle-income countries and often have limited access to healthcare.2,3 Nearly 6 million of these children receive at least one vaccine dose, but remain at risk because they have not completed the full dosing regimen.4,5 A vaccination method that delivers all doses of a vaccine, or multiple vaccines, in a single injection would enable children with even one-time access to healthcare to be fully protected from the corresponding infectious disease. Unfortunately, most controlled-release drug delivery systems exhibit continuous release kinetics, which is vastly different from traditional soluble vaccines administered in multiple discrete doses over a course of months. One recent study has described the development of biodegradable microparticle platform with a polymer shell encapsulating a vaccine-loaded core that exhibits delayed, pulsatile release after a period determined by the polymer degradation rate.6 By injecting patients with a mixed population of particles with different degradation rates, vaccine can be released as discrete pulses, thereby mimicking traditional vaccination schedules known to be safe and effective. Unfortunately, the original microparticle production method negatively affects antigen stability, requires the use of large-gauge needles, and is low-throughput. This project seeks to overcome these challenges by preparing microparticles using coaxial electrospraying, a single-step fabrication process that can produce a single aqueous, vaccine-loaded core surrounded by a shell of polymer. This proposal first aims to create small core-shell microparticles with dense polymeric shells that demonstrate the delayed, pulsatile release of macromolecules in vitro and in vivo. Fluorescently tagged proteins will be used as model vaccines to study the effects of particle size, shell density, relative wall thickness, and post-processing on release kinetics. After identifying formulations that achieve pulsatile release, we will then optimize processing conditions to maximize encapsulated antigen stability. An enzymatic reporter and a pH-sensitive dye will be added to the core and tested at several stages of the particle life cycle to monitor microenvironmental conditions during fabrication, storage, and release. Electrospraying materials and parameters will be adjusted to minimize changes to protein conformation that could result from solvent interactions, thermal instability, and particle acidification, which may affect the immune system's ability to create neutralizing antibodies. Although further optimization will be required to fine-tune conditions for specific vaccines, this project will provide a framework for quickly developing controlled-release vaccine formulations. Ultimately, these particles could serve as a key tool in the fight against infectious disease both in the developing world where resources are limited and in the developed world, where uninsured children and rural communities show consistently lower vaccination coverage.7

项目概要/摘要 每年估计有 1940 万儿童没有接种世界推荐的疫苗 卫生组织，导致 150 万人因疫苗可预防的死亡。1,2 大多数儿童未接种疫苗 生活在低收入和中等收入国家，获得医疗保健的机会往往有限。2,3 其中近 600 万人 儿童至少接受了一剂疫苗，但由于尚未完成全部剂量，因此仍面临风险 方案 4,5 在单次注射中提供所有剂量的疫苗或多种疫苗的疫苗接种方法 将使即使是一次性获得医疗保健的儿童也能得到充分保护，免受相应的影响 传染病。不幸的是，大多数控释药物递送系统表现出连续释放 动力学，这与传统的可溶性疫苗在一段时间内以多个离散剂量施用有很大不同 几个月的过程。最近的一项研究描述了可生物降解微粒平台的开发 聚合物外壳封装了负载疫苗的核心，在一段时间后表现出延迟的脉冲释放 由聚合物降解率决定。6 通过向患者注射混合颗粒群 不同的降解率，疫苗可以作为离散脉冲释放，从而模仿传统的疫苗接种 已知安全有效的时间表。不幸的是，原来的微粒生产方法产生了负面影响 影响抗原稳定性，需要使用大规格针头，且通量低。该项目旨在 通过使用同轴电喷雾（一步制造）制备微粒来克服这些挑战 该过程可以产生一个由聚合物壳包围的单一水性、负载疫苗的核心。这个提议 首先的目标是创造具有致密聚合物壳的小核壳微粒，以证明延迟， 体外和体内大分子的脉冲释放。荧光标记的蛋白质将用作模型 研究颗粒大小、壳密度、相对壁厚和后处理对释放的影响的疫苗 动力学。在确定实现脉冲释放的配方后，我们将优化加工条件 最大限度地提高封装抗原的稳定性。酶报告剂和 pH 敏感染料将被添加到 核心并在颗粒生命周期的多个阶段进行测试，以监测期间的微环境条件 制造、储存和发布。将调整电喷涂材料和参数以尽量减少变化 溶剂相互作用、热不稳定性和颗粒酸化可能导致的蛋白质构象， 这可能会影响免疫系统产生中和抗体的能力。虽然进一步优化将 如果需要微调特定疫苗的条件，该项目将提供一个快速框架 开发控释疫苗制剂。最终，这些粒子可以作为关键工具 在资源有限的发展中国家和发达国家与传染病作斗争 在世界各地，未参保的儿童和农村社区的疫苗接种覆盖率一直较低。7