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

项目概要/摘要 流感相关的免疫应答缺陷导致老年人流感疫苗的有效性降低 成年人了甲型流感病毒（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 为老年人提供安全有效的疫苗以增强保护性免疫力是一项紧迫的公共卫生需求。 修订后的R 01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 与年龄相关的免疫缺陷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分支，并提供一个平台，以扩大抗原选择，扩大 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效力产生保护。目标是：1）制定一个 对老年人有效的流感纳米疫苗; 2）了解 合理选择疫苗中的生物材料和辅助佐剂可增强老年人的免疫能力 个体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，已被证明可以增加抗体滴度，改善细胞介导的免疫，并延长抗原 在递送重组体时，递送导致保护性免疫应答， 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树突细胞（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DC代谢， 老年小鼠的免疫反应。不同的疫苗配方将比较产生高剂量的佐剂。 糖酵解反应与制剂保留一些氧化磷酸化和备用呼吸 优化DC功能。在第二个目标中，我们将优化纳米疫苗制剂， 增强老年小鼠中的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T滤泡辅助反应和诱导 保护性免疫力传统的灭活IAV疫苗将用作对照， 以鉴定提供比现有疫苗更好的上级保护的制剂。在目标3中，我们将确定 纳米疫苗诱导的代谢优化的DC-T细胞引发如何有助于T细胞记忆， 老年小鼠抗IAV的异源保护。病毒载量、血清抗体和肺T细胞测量 将在老年小鼠中的同源和异亚型IAV攻击中评价应答。长期 本研究的目的是确定诱导保护性免疫应答的机制， 这有助于为这些得不到充分服务的人群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.