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

项目摘要/摘要 每年估计有1,940万儿童未收到世界推荐的疫苗 卫生组织，导致150万疫苗可预防的死亡。1,2大多数不受欢迎的儿童 生活在低收入和中等收入国家，经常获得医疗保健的机会。2,3近600万 儿童至少接受一次疫苗剂量，但由于尚未完成全部剂量而保持危险 方案4,5一种疫苗接种方法，可在一次注射中输送所有剂量的疫苗或多种疫苗 即使是一次性获得医疗保健的儿童，可以完全保护相应的医疗保健 传染病。不幸的是，大多数受控药物输送系统表现出连续释放 动力学，与以多种离散剂量给药的传统可溶性疫苗有很大不同 几个月的课程。一项最近的一项研究描述了可生物降解的微粒平台的发展 封装疫苗的芯壳的聚合物壳，该芯芯在一段时间后表现出延迟的脉动释放 由聚合物降解速率确定。6 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，原始的微粒生产方法负面 影响抗原稳定性，需要使用大型针头，并且是低通量的。这个项目试图 通过使用同轴电喷雾（单步制造）制备微粒来克服这些挑战 可以产生单个水性，疫苗的芯子的过程，该核心被聚合物壳包围。这个建议 首先旨在创建带有密集的聚合物壳的小核壳微粒，以证明延迟， 大分子在体外和体内的脉冲释放。荧光标记的蛋白将用作模型 疫苗研究粒径，壳密度，相对壁厚和后处理对释放的影响 动力学。在确定了获得脉动释放的配方后，我们将优化处理条件 最大化封装的抗原稳定性。酶促报告基因和pH敏感染料将被添加到 核心并在粒子生命周期的多个阶段进行了测试，以监测微环境条件 制造，存储和释放。电喷雾材料和参数将进行调整以最大程度地减少变化 蛋白质构象可能是由于溶剂相互作用，热不稳定性和颗粒酸化所致的蛋白质构象， 这可能会影响免疫系统创建中和抗体的能力。尽管进一步的优化将 要求对特定疫苗进行微调条件，该项目将为快速提供一个框架 开发受控释放的疫苗配方。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的发展中国家中对抗传染病 世界上，没有保险的儿童和农村社区表现出持续较低的疫苗接种覆盖范围。7