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

项目摘要/摘要 与年龄相关的免疫反应缺陷导致流感疫苗在老年人中的效力降低 成年人。甲型流感病毒(IAV)感染导致更大的并发症风险和更高的住院率 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 研制一种安全有效的疫苗，促进老年人的保护性免疫，是一项紧迫的公共卫生需求。 这一修订的R01应用的总体目标是确定疫苗生物材料和佐剂对 树突状细胞的代谢，以及随后对抗体和T细胞记忆的影响，开发出一种能够克服的纳米疫苗 与年龄相关的免疫损伤。老年人的疫苗可以用生物材料进一步优化， 增强免疫系统的多个手臂，并提供一个扩大抗原选择的平台，扩大 保护。我们的研究将确定特定的生物材料和佐剂在改善B和 T细胞结果通过增强疫苗效力而产生保护作用。目标是：1)开发一种 为老年人提供有效的纳米流感疫苗；以及2)了解 疫苗中合理选择生物材料和辅助剂可提高老年人的免疫能力 个人。我们的两个聚合物纳米疫苗平台，聚酸酐纳米颗粒和五嵌段共聚物 胶束，已被证明可以提高抗体效价，改善细胞免疫，延长抗原。 递送导致保护性免疫反应，在递送重组人时降低病毒载量 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。目标 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 衰老小鼠的免疫反应。不同的疫苗配方将比较高产量的佐剂 保留部分氧化磷酸化和备用呼吸的制剂的糖酵解反应 优化DC功能的容量。在第二个目标中，我们将优化纳米疫苗配方(S)， 增强老龄小鼠和老龄人类外周血中B细胞的活性。此外，我们还将 确定我们的纳米疫苗改善T滤泡辅助反应和诱导 在老龄化背景下的保护性免疫。将使用传统的IAV灭活疫苗作为对照，以 以确定提供比当前疫苗更好保护的配方。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 对老龄小鼠IAV的异种保护作用。病毒载量、血清抗体和肺T细胞的测定 将在老年小鼠中评估同源和异型IAV挑战的反应。长期的 这项研究的目的是确定引起保护性免疫反应的机制。 人口老龄化，从而促进为这一服务不足的人口合理设计改进的疫苗。

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.