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 本研究的目的是研究年龄对脂类所需递送过程的影响。 纳米颗粒介导的信使核糖核酸疫苗接种，长期目标是改善疫苗接种结果 老年人。未来30年，我们的老年人口将翻一番，全球老年人口将超过16亿。 不幸的是，免疫系统的衰退使老年人容易感染一系列致命的传染性疾病。 疾病，给全球医疗保健带来了额外的负担，特别是在流行病和诸如 如埃博拉和SARS-CoV-2。确实需要有效的预防措施来保护弱势群体。 信使核糖核酸(Messenger RNA，mRNA)已经成为一个革命性的平台，它催化了最快的发展 这是历史上疫苗最多的一次，支持了抗击SARS-CoV-2病毒的斗争。然而，早期的数据表明，这些 疫苗会引起年龄相关的免疫反应。这些疫苗的抗体反应减弱 老年人可以大大缩短他们的保护期。迫切需要了解mrna。 随着年龄的增长而递送，并开发有效且安全的疫苗，可以保护所有年龄段的人 组。当其他研究人员正在检查与年龄相关的免疫系统损伤时，这项研究是 独一无二的是因为它将确定与年龄相关的对脂质纳米粒(LNP)mRNA传递的影响 进程。这将使受损的递送和减弱的对mRNA的免疫反应脱钩。 在老年人中接种疫苗。我已经准备好进行这项研究，考虑到我的初步数据和 怀特黑德和魏斯曼实验室在LNP递送、免疫学和疫苗接种方面的专业知识。 尽管测量接种后感染率和抗体滴度作为年龄的函数 重要的是，这些终点没有捕捉到年龄对mRNA过程中关键中间步骤的影响 接种疫苗。我推测，不同的递送方式会降低信使核糖核酸诱导的免疫力。至 检验这一假设，我将确定年龄对脂质纳米颗粒mRNA传递终点(AIM)的影响程度 1)和免疫反应(目标2)，使两者脱钩。在目标1中，我将确定其疗效， 五种性能最好的脂质纳米粒的生物分布、靶向细胞群、免疫原性和毒性 在幼年和老年小鼠肌肉注射后，无论性别。在目标2中，我将阐明 年龄对mRNA-LNPs免疫应答的影响。从AIM 2.1中，我们将选择表现最好的LNP进行调查 进一步的疫苗动力学研究(目标2.2)。目标1和目标2结合在一起将揭示LNP结构，这些结构赋予 小鼠和老年小鼠最强大的免疫反应，并有助于更有效的mRNA的开发 为老年人接种疫苗。 这项工作是创新的，因为我们将研究年龄如何影响纳米颗粒的传递过程，这已经 对mRNA-LNPs的研究尚未全面展开。从长远来看，我们的发现将具有临床意义 这具有重要意义，因为它们将有助于为老年人量身定制LNP提供系统的设计。