Overcoming Immunosenescence by Nanoparticle-Mediated Activation

描述(由申请人提供)： 疫苗设计的一个新挑战是为不断增长的老年人口开发有效的疫苗。流感是一种高度传染性的呼吸道病毒感染，每年影响全球300万至500万人，造成20万至50万人死亡。老年人(65岁)尤其容易感染严重的流感。现在有强有力的证据表明，季节性H1N1流感疫苗对这些老年受试者基本上无效，使他们面临并发症、住院和死亡的高风险。目前流感疫苗在老年人中的无效与免疫衰老有关，免疫衰老是一种与年龄相关的免疫系统逐渐恶化。人们越来越相信，一些导致免疫衰老的关键限制可以通过改进免疫策略来克服，例如使用新型佐剂来促进有效的记忆免疫。目前的佐剂通常通过激活疫苗接种部位的树突状细胞(DC)，并加强抗原负载的DC向引流淋巴结(DLN)的运输来发挥作用，DLN是获得性免疫反应的中心，也是抗原呈递给T细胞的地方。在这里，我们提出了一种替代策略来加速和最大化免疫反应。我们最近开发了一种颗粒介导的疫苗系统，能够在接种期间将关键的免疫刺激细胞因子直接运送到DLN。这种佐剂技术使老龄小鼠的DLN发生了快速而显著的组织变化，老年小鼠是不像人类同类动物那样免疫反应的动物。靶向递送这些免疫调节剂所引起的DLN的变化与强大的免疫反应是一致的，包括不仅DC而且T细胞的积极和持续的招募。这项建议的目的是开发一种有效的免疫刺激策略和佐剂配方，具有克服免疫衰老的潜力。其具体目标是：1)利用各种免疫调节介质的组合优化生物相容和可降解纳米粒的组成、尺寸和载药量，以实现在DLN中的最大释放和控制释放；2)展示由季节性流感疫苗和各种细胞因子负载的纳米粒组成的疫苗配方在促进老龄小鼠最大免疫方面的安全性和有效性；3)评估流感疫苗与淋巴激活纳米粒联合使用在保护老龄小鼠免受致命流感病毒感染方面的预防和治疗能力。如果被证明是成功的，这种方法可能成为改进疫苗的新范例。

DESCRIPTION (provided by applicant): One new challenge for vaccine design is the development of effective vaccines for the ever growing geriatric population. Influenza is a highly contagious viral infection of the respiratory tract that afflicts 3-5 million people world-wide with 200,000-500,000 deaths each year. The elderly (>65 years) are especially prone to severe influenza infection. There is now strong evidence that the seasonal H1N1 influenza vaccine is largely ineffective for these elderly subjects, subjecting them to high risk of complication, hospitalization and death. The ineffectiveness of current flu vaccines in the elderly has been associated with immunosenescence, which is a gradual age-associated deterioration of the immune system. There is growing belief that some of the key limitations resulting in immunosenescence can be overcome by improved immunization strategies, such as the use of novel adjuvants to promote effective memory immunity. Current adjuvants typically work by activating dendritic cells (DCs) at the site of vaccine administration and enhancing the trafficking of antigen-loaded DCs to the draining lymph nodes (DLNs), the epicenter of the adaptive immune response and where antigen presentation to T cells occurs. Here, we propose an alternate strategy to accelerate and maximize the immune responses. We recently developed a particle-mediated vaccine system capable of transporting critical immunostimulatory cytokines directly to the DLN during vaccination. This adjuvant technology induced rapid and significant organizational changes to the DLNs of aged mice, animals that are not immunoresponsive, like their human counterparts. The changes in the DLNs induced by targeted delivery of these immunomodulators were consistent with robust immune responses, including vigorous and sustained recruitment of not only DCs but also T cells. The objective of this proposal is to develop an effective immune stimulatory strategy and adjuvant formulation with the potential of overcoming immunosenescence. The Specific aims are: 1) Optimize the composition, size and loading of biocompatible and degradable nanoparticles with various combinations of immunodulatory mediators to achieve maximal delivery and controlled release in the DLNs; 2) Demonstrate the safety and efficacy of a vaccine formulation comprising the seasonal Flu vaccine and various cytokine-loaded nanoparticles in promoting maximal immunity in aged mice; 3) Evaluate the prophylactic and therapeutic ability of the flu vaccine in combination with lymph node activating nanoparticles in protecting aged mice against lethal influenza virus infections. If proven successful, this approach could serve as a new paradigm for improving vaccines in general.