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，每年在全球范围内折磨300 - 500万人，造成20万-50万人死亡。老年人（>65岁）特别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无效，使他们面临并发症、住院和死亡的高风险。目前的流感疫苗在老年人中的无效性与免疫衰老有关，这是一种与年龄相关的免疫系统逐渐恶化。越来越多的人相信，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在疫苗施用部位激活树突状细胞（DC）并增强负载抗原的DC向引流淋巴结（DLN）的运输而起作用，所述引流淋巴结是适应性免疫应答的中心并且在此处发生抗原呈递给T细胞。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，能够在疫苗接种过程中将关键的免疫刺激细胞因子直接转运到DLN。这种佐剂技术诱导了老年小鼠DLN的快速和显著的组织变化，老年小鼠是没有免疫应答的动物，就像它们的人类同行一样。通过靶向递送这些免疫调节剂诱导的DLN的变化与稳健的免疫应答一致，包括不仅DC而且T细胞的剧烈和持续的募集。本提案的目的是开发一种有效的免疫刺激策略和具有克服免疫衰老潜力的佐剂制剂。具体目标是：1）优化具有免疫调节介质的各种组合的生物相容性和可降解的纳米颗粒的组成、尺寸和负载，以实现DLN中的最大递送和受控释放; 2）证明包含季节性流感疫苗和各种负载精氨酸的纳米颗粒的疫苗制剂在促进老年小鼠的最大免疫力中的安全性和功效; 3）评估流感疫苗与淋巴结活化纳米颗粒组合在保护老年小鼠免受致死性流感病毒感染方面的预防和治疗能力。如果证明成功，这种方法可以作为改进疫苗的新范例。 公共卫生相关性： 许多疫苗对老年患者（>65岁）无效，因为免疫衰老，一种与年龄相关的免疫系统逐渐恶化。我们已经开发了一种颗粒介导的佐剂技术，该技术能够将关键的免疫刺激细胞因子直接递送至引流淋巴结，该引流淋巴结是适应性免疫应答的中心，并且是发生抗原呈递至T细胞的地方。通过加速和最大化对先前无应答亚群的免疫应答，这种疫苗技术可以显着改善老年患者的医疗保健。

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. PUBLIC HEALTH RELEVANCE: Relevance to Healthcare Many vaccines are ineffective in elderly patients (>65 years) because of immunosenescence, a gradual age-associated deterioration of the immune system. We have developed a particle- mediated adjuvant technology capable of delivering critical immunostimulatory cytokines directly to the draining lymph node, the epicenter of the adaptive immune response and where antigen presentation to T cells occurs. By accelerating and maximizing the immune responses to previously non-responsive subpopulations, this vaccine technology may significantly improve the healthcare of elderly patients.