Combination nanovaccine-based immunization against influenza virus in the aged: immunity and protection

基于纳米疫苗的老年人流感病毒联合免疫：免疫与保护

• 批准号: 10553681
• 负责人: Marian L Kohut
• 金额: $ 71.62万
• 依托单位: IOWA STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-02-16 至 2026-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10553681
• 关键词: Adjuvant; Adult; Aging; Antibodies; Antibody Formation; Antibody Response; Antibody titer measurement; Antigen Presentation; Antigens; B-Cell Activation; B-Lymphocytes; Biocompatible Materials; Biology of Aging; Blood; CD8-Positive T-Lymphocytes; Cell physiology; Cellular Immunity; Cellular Metabolic Process; Cessation of life; Characteristics; Clinical Trials; Data; Defect; Dendritic Cells; Development; Dose; Elderly; Formulation; Goals; Health; Helper-Inducer T-Lymphocyte; Hemagglutinin; Human; Immune; Immune response; Immune system; Immunity; Immunization; Impairment; In Vitro; Individual; Infection; Inflammation; Inflammatory; Influenza; Influenza A virus; Influenza vaccination; Lead; Lung; Measures; Memory; Metabolic; Micelles; Mitochondria; Modeling; Mus; Nucleoproteins; Older Population; Outcome; Outcome Measure; Oxidative Phosphorylation; Phenotype; Polyanhydrides; Population; Public Health; Publishing; Recombinants; Research; Respiration; Risk; Role; Route; Serum; Spleen; T cell response; T memory cell; T-Cell Activation; T-Lymphocyte; Testing; Underserved Population; Vaccines; Viral Load result; Virus Diseases; adaptive immunity; age related; aged; amphiphilicity; arm; cell age; cell motility; copolymer; design; draining lymph node; flexibility; hospitalization rates; human old age (65+); immunogenicity; improved; influenza infection; influenza virus vaccine; influenzavirus; insight; lymph nodes; metabolic profile; mortality; nanoparticle; nanopolymer; nanovaccine; nonhuman primate; novel; novel strategies; peripheral blood; preservation; primary outcome; rational design; respiratory; response; safety study; self assembly; vaccine delivery; vaccine efficacy; vaccine formulation; vaccine platform; vaccine response; vaccine-induced immunity; young adult

PROJECT SUMMARY / ABSTRACT Age-related defects of the immune response contribute to reduced efficacy of the influenza vaccine in older adults. Influenza A virus (IAV) infection results in greater risk of complications and higher hospitalization rates in older adults, with approximately 90% of deaths occurring in adults over age 65. Therefore, the development of a safe and effective vaccine that promotes protective immunity for the aged is an urgent public health need. The overall goal of this revised R01 application is to identify the effect of vaccine biomaterials and adjuvants on DC metabolism, and subsequent effects on antibody and T cell memory to develop a nanovaccine to overcome age-related immune impairments. Vaccines for older adults can be further optimized with biomaterials that enhance multiple arms of the immune system and provide a platform to expand antigen selection, broadening protection. Our studies will establish the contribution of specific biomaterials and adjuvants in improving B and T cell outcomes resulting in protection by enhancing vaccine efficacy. The goals are to: 1) develop an efficacious influenza nanovaccine for older populations; and 2) to understand the mechanisms by which rational selection of biomaterials and co-adjuvants in vaccines can enhance immune capabilities of aged individuals. Our two polymeric nanovaccine platforms, polyanhydride nanoparticles and pentablock copolymer micelles, have been shown to increase antibody titers, improve cell-mediated immunity, and prolong antigen delivery resulting in a protective immune response with reduced viral load upon delivery of recombinant hemagglutinin and nucleoprotein in an IAV challenge model. Compelling preliminary data demonstrates that these formulations differentially alter dendritic cell (DC) metabolic profile compared to traditional adjuvants. Aim 1 will identify how nanovaccine biomaterials and adjuvants that promote DC metabolic health augment the immune response in aged mice. Different vaccine formulations will compare adjuvants that produce high glycolytic responses with formulations that retain some oxidative phosphorylation and spare respiratory capacity to optimize DC function. In the second aim, we will optimize the nanovaccine formulation(s) that enhance B cell activation in aged mice and peripheral blood B cells from aged humans. Additionally, we will identify mechanisms by which our nanovaccine improves T follicular helper responses and the induction of protective immunity on an aging background. Traditional inactivated IAV vaccine will be used as a control so as to identify the formulation providing superior protection than the current vaccine. In Aim 3, we will determine how nanovaccine-induced metabolically-optimized DC-T cell priming contributes to T cell memory and heterologous protection against IAV in aged mice. Measures of viral load, serum antibody, and lung T cell responses will be evaluated in homologous and heterosubtypic IAV challenges in aged mice. The long-term goal of this research is to define the mechanisms responsible for induction of protective immune responses in aging populations, thus facilitating the rational design of improved vaccines for this underserved population.

项目概要/摘要 与年龄相关的免疫反应缺陷导致老年人流感疫苗的功效降低 成年人。甲型流感病毒 (IAV) 感染会导致更大的并发症风险和更高的住院率 老年人中，大约 90% 的死亡发生在 65 岁以上的成年人中。因此，发展 开发一种安全有效的疫苗来促进老年人的保护性免疫力是迫切的公共卫生需求。 此次修订的 R01 申请的总体目标是确定疫苗生物材料和佐剂对 DC代谢以及随后对抗体和T细胞记忆的影响，以开发纳米疫苗来克服 与年龄相关的免疫损伤。可以使用生物材料进一步优化老年人疫苗 增强免疫系统的多个分支，并提供一个扩大抗原选择的平台，拓宽 保护。我们的研究将确定特定生物材料和佐剂在改善 B 和 T 细胞结果通过增强疫苗功效来产生保护。目标是：1）开发 对老年人群有效的流感纳米疫苗； 2）了解其机制 疫苗中生物材料和辅佐剂的合理选择可增强老年人的免疫能力 个人。我们的两个聚合物纳米疫苗平台，聚酐纳米颗粒和五嵌段共聚物 胶束已被证明可以增加抗体滴度，改善细胞介导的免疫，并延长抗原 递送导致保护性免疫反应，并在递送重组体时减少病毒载量 IAV 攻击模型中的血凝素和核蛋白。令人信服的初步数据表明 与传统佐剂相比，这些制剂不同地改变了树突状细胞（DC）的代谢特征。目的 1 将确定促进 DC 代谢健康的纳米疫苗生物材料和佐剂如何增强 老年小鼠的免疫反应。不同的疫苗配方将比较产生高效果的佐剂 使用保留一些氧化磷酸化和保护呼吸的制剂来抑制糖酵解反应 优化 DC 功能的能力。在第二个目标中，我们将优化纳米疫苗配方， 增强老年小鼠 B 细胞和老年人外周血 B 细胞的活化。此外，我们将 确定我们的纳米疫苗改善滤泡辅助 T 反应和诱导 老龄化背景下的保护性免疫力。将使用传统灭活 IAV 疫苗作为对照，以便 以确定比现有疫苗提供更好保护的配方。在目标 3 中，我们将确定 纳米疫苗诱导的代谢优化 DC-T 细胞启动如何促进 T 细胞记忆和 对老年小鼠 IAV 的异源保护。病毒载量、血清抗体和肺 T 细胞的测量 将在老年小鼠的同源和异亚型 IAV 攻击中评估反应。长期来看 这项研究的目标是确定诱导保护性免疫反应的机制 人口老龄化，从而有助于为这一服务不足的人群合理设计改进的疫苗。