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质所需的分娩过程的影响。 纳米颗粒介导的mRNA疫苗接种，其长期目标是改善 老人在未来30年，我们的老年人口将翻一番，超过16亿人。 不幸的是，免疫系统的下降使老年人容易受到一系列致命的传染病的影响。 疾病，给全球卫生保健带来额外负担，特别是在流行病和大流行病期间， 埃博拉和SARS-CoV-2。真实的需要有效的预防措施来保护弱势群体。 信使RNA（mRNA）已经成为一个革命性的平台，催化了最快的发展 并支持了抗击SARS-CoV-2的斗争。然而，早期数据表明，这些 疫苗引发年龄依赖性免疫应答。这些疫苗的抗体反应减弱， 长者可大大缩短保障期。迫切需要了解mRNA 根据年龄提供疫苗，并开发有效和安全的疫苗，可以保护所有年龄段的人 组当其他研究人员正在研究与年龄相关的免疫系统损伤时，这项研究是 独特的，因为它将确定脂质纳米颗粒（LNP）mRNA递送的年龄相关效应 过程这将使受损的递送和mRNA上减弱的免疫应答脱钩 老年人接种疫苗。我准备好进行这项研究，鉴于我的初步数据和 Whitehead和Weissman实验室在LNP递送、免疫学和疫苗学方面的专业知识。 虽然测量接种后感染率和抗体滴度作为年龄的函数是可行的， 重要的是，这些终点并没有捕捉到年龄对mRNA表达过程中关键中间步骤的影响。 预防针我推测，不同的交付有助于减少mRNA诱导的免疫力。到 为了验证这一假设，我将确定年龄在多大程度上影响脂质纳米颗粒mRNA递送终点（Aim 1)和免疫反应（目标2），使两者脱钩。在目标1中，我将确定疗效， 五种性能最佳的脂质纳米粒的生物分布、靶向细胞群、免疫原性和毒性 在两种性别的年轻和年老小鼠中肌内注射后。在目标2中，我将阐明 年龄对mRNA-LNP免疫应答的影响。从目标2.1中，我们将选择一个性能最佳的LNP进行研究 进一步在疫苗动力学研究中（目标2.2）。目标1和2结合起来将揭示LNP的结构， 在年轻和年老的小鼠中最强大的免疫反应，并帮助开发更有效的mRNA 老年人的疫苗。 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输送的过程， 尚未对mRNA-LNP进行全面研究。从长远来看，我们的发现将具有临床意义。 这是一项重要的工作，因为它们将有助于为老年人量身定制LNP输送系统的设计。