Effects of Age on Lipid Nanoparticle Delivery and mRNA Vaccination

年龄对脂质纳米颗粒递送和 mRNA 疫苗接种的影响

• 批准号: 10605919
• 负责人: Mariah Arral
• 金额: $ 4.38万
• 依托单位: CARNEGIE-MELLON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-01-01 至 2024-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10605919
• 关键词: 2019-nCoV; Affect; Age; Aging; Antibody Response; Antibody titer measurement; Biodistribution; Biological; Biological Assay; Cells; Circulation; Clinical; Communicable Diseases; Data; Development; Dose; Ebola; Elderly; Enzyme-Linked Immunosorbent Assay; Epidemic; Flow Cytometry; Foreign Bodies; Formulation; Goals; Healthcare; Immune; Immune response; Immune system; Immunity; Immunologics; Immunology; Impairment; Intramuscular; Intramuscular Injections; Kinetics; Measures; Mediating; Memory; Memory B-Lymphocyte; Messenger RNA; Methods; Modeling; Mus; Outcome; Ovalbumin; Patients; Performance; Persons; Pharmaceutical Preparations; Physiological; Population; Positioning Attribute; Predisposition; Process; Proteins; RNA delivery; RNA vaccination; RNA vaccine; Recording of previous events; Reporter; Research; Research Personnel; Serology; Structure; Subgroup; System; T-Lymphocyte; Testing; Therapeutic; Time; Tissues; Toxic effect; Toxicology; Transfection; Vaccination; Vaccine Production; Vaccines; Variant; Vulnerable Populations; Work; age effect; age group; age related; clinically significant; cytokine; design; dosage; efficacy evaluation; experience; fighting; global health; human old age (65+); immune activation; immunogenic; immunogenicity; improved; in vivo imaging; infection rate; innovation; lipid nanoparticle; nanoparticle; nanoparticle delivery; nanoprocess; next generation; pandemic disease; prophylactic; response; senescence; sex; uptake; vaccination outcome; vaccine development; vaccine efficacy; vaccine immunogenicity; vaccine response; vaccinology; young adult

PROJECT ABSTRACT The goal of this research is to study the influence of age on the delivery processes required for lipid nanoparticle-mediated mRNA vaccination, with a long-term goal of improving vaccination outcomes in the elderly. In the next thirty years, our elderly population will double, exceeding 1.6 billion people worldwide. Unfortunately, a declining immune system makes elderly people susceptible to an array of deadly infectious diseases, placing additional burdens on global healthcare, particularly during epidemics and pandemics such as Ebola and SARS-CoV-2. There is a real need for effective prophylactics that protect vulnerable populations. Messenger RNA (mRNA) has emerged as a revolutionary platform that has catalyzed the fastest development of vaccines in history and bolstered the fight against SARS-CoV-2. However, early data suggest that these vaccines elicit an age-dependent immune response. The diminished antibody response of these vaccines in the elderly can substantially curtail their duration of protection. There is an urgent need to understand mRNA delivery as a function of age and develop potent and safe vaccines that can protect people across all age groups. While other researchers are examining age-related immune system impairment, this research is unique because it will determine age-related effects on the lipid nanoparticle (LNP) mRNA delivery process. This will enable the decoupling of impaired delivery and diminished immune responses on mRNA vaccination in the elderly. I am well-poised to conduct this research, given my preliminary data and the expertise of the Whitehead and Weissman labs with LNP delivery, immunology, and vaccinology. Although measuring post-vaccination infection rates and antibody titers as a function of age is important, these endpoints do not capture the effect of age on critical intermediate steps during mRNA vaccination. I hypothesize that differences in delivery contribute to reductions in mRNA-induced immunity. To test this hypothesis, I will determine to what extent age affects lipid nanoparticle mRNA delivery endpoints (Aim 1) and immune responses (Aim 2), allowing the two to be decoupled. In Aim 1, I will determine the efficacy, biodistribution, targeted cell population, immunogenicity, and toxicity of five top-performing lipid nanoparticles following intramuscular injection in young and old mice of both sexes. In Aim 2, I will elucidate the impact of age on the immune response of mRNA-LNPs. From Aim 2.1, we will select a top-performing LNP to investigate further in a vaccine kinetics study (Aim 2.2). Aims 1 and 2 combined will reveal LNP structures that confer the most robust immune response in young and old mice and aid the development of more efficacious mRNA vaccines for the elderly. This work is innovative because we will study how age impacts the process of nanoparticle delivery, which has not been conducted comprehensively for mRNA-LNPs. In the long term, our discoveries will have clinical significance because they will help tailor the design of LNP delivery systems for the elderly.

项目摘要 这项研究的目的是研究年龄对脂质所需的交付过程的影响 纳米粒子介导的mRNA疫苗接种，其长期目标是改善疫苗接种结果 老年。在接下来的三十年中，我们的老年人口将翻一番，全球超过16亿人口。 不幸的是，一个衰落的免疫系统使老年人容易受到一系列致命感染的影响 疾病，给全球医疗保健带来额外的负担，尤其是在流行病和大流行期间 作为埃博拉病毒和SARS-COV-2。真正需要有效的预防药物来保护脆弱的人群。 Messenger RNA（mRNA）已成为一个革命平台，它催化了最快的发展 历史上的疫苗，并加强了与SARS-COV-2的战斗。但是，早期数据表明这些 疫苗会引起年龄依赖性免疫反应。这些疫苗在 老年人可能会大大削减保护持续时间。迫切需要了解mRNA 随着年龄的函数交付并开发有效且安全的疫苗，可以保护所有年龄段的人 组。尽管其他研究人员正在检查与年龄相关的免疫系统损害，但该研究是 唯一，因为它将确定与年龄相关的脂质纳米颗粒（LNP）mRNA递送的影响 过程。这将使分娩受损并减少mRNA的免疫反应的脱钩 老年人的疫苗接种。鉴于我的初步数据和 Whitehead和Weissman Labs具有LNP输送，免疫学和疫苗学的专业知识。 尽管测量疫苗接种后感染率和抗体滴度随着年龄的影响是 重要的是，这些终点不会捕获年龄对mRNA期间关键中间步骤的影响 疫苗接种。我假设输送的差异导致mRNA诱导的免疫力的降低。到 检验该假设，我将确定年龄在多大程度上影响脂质纳米粒子mRNA递送终点（AIM 1）和免疫反应（AIM 2），使两者被解耦。在AIM 1中，我将确定功效， 生物分布，靶向细胞种群，免疫原性和五个表现最佳脂质纳米颗粒的毒性 两性男女的年轻小鼠和老鼠肌内注射后。在AIM 2中，我将阐明 mRNA-LNP的免疫反应的年龄。在AIM 2.1中，我们将选择一个表现最佳的LNP来调查 进一步的疫苗动力学研究（AIM 2.2）。目标1和2组合将揭示赋予该结构的LNP结构 年轻人和老鼠中最强大的免疫反应，并帮助发展更有效的mRNA 老年人的疫苗。 这项工作具有创新性，因为我们将研究年龄如何影响纳米颗粒传递过程 对于mRNA-LNP，未全面进行。从长远来看，我们的发现将有临床 意义是因为它们将有助于定制老年人的LNP输送系统的设计。