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.

项目摘要 /摘要 免疫反应与年龄相关的缺陷有助于降低流感疫苗在老年人中的疗效 成年人。流感病毒（IAV）感染会导致并发症的风险更大和住院率更高 在老年人中，大约90％的死亡发生在65岁以上的成年人中。因此，发展 紧急的公共卫生需求是促进老年人保护性免疫的安全有效疫苗。 此修订后的R01应用的总体目标是确定疫苗生物材料和佐剂对 直流代谢，以及随后对抗体和T细胞记忆的影响，以开发纳米霉素以克服 与年龄有关的免疫障碍。可以通过生物材料进一步优化老年人的疫苗 增强免疫系统的多个臂，并提供一个平台来扩展抗原选择，扩大 保护。我们的研究将确定特定生物材料和辅助因子在改善B和 T细胞结局通过增强疫苗功效而导致保护。目标是：1）开发 有效的流感纳米霉素适用于老年人群； 2）了解 疫苗中生物材料和共助剂的合理选择可以增强衰老的免疫能力 个人。我们的两个聚合物纳米甲虫平台，多丙二醇纳米颗粒和五角杆共聚物 已显示胶束可增加抗体滴度，改善细胞介导的免疫力并延长抗原 递送后，导致保护性免疫反应，重组后病毒负荷减少 IAV挑战模型中的血凝素和核蛋白。引人入胜的初步数据表明 与传统佐剂相比，这些配方差异改变了树突状细胞（DC）代谢谱。目的 1将确定纳米酮生物材料和辅助剂如何促进直流代谢健康的增强 老年小鼠的免疫反应。不同的疫苗配方将比较产生高的佐剂 糖酵解反应与保留一些氧化磷酸化和备用呼吸的制剂 优化直流功能的能力。在第二个目的中，我们将优化纳米霉素配方 增强了老年人的老年小鼠和外周血B细胞的B细胞活化。此外，我们会的 确定我们的纳米酮改善卵泡辅助反应的机制，并诱导 在老化背景下的保护性免疫。传统的灭活IAV疫苗将被用作控制 确定与当前疫苗相比，提供优质保护的配方。在AIM 3中，我们将确定 纳米霉素诱导的新陈代谢优化的DC-T细胞启动如何有助于T细胞记忆和 对年龄小鼠的IAV的异源保护。病毒负荷，血清抗体和肺T细胞的测量 将在老年小鼠的同源和异源性IAV挑战中评估反应。长期 这项研究的目标是定义负责诱导保护性免疫反应的机制 老龄化的人口，从而促进了这一服务不足的人群改善疫苗的合理设计。