Optimizing a Universal Influenza Subunit Nano/Microparticulate Vaccine

摘要 世卫组织估计，每年约有500万例流感感染病例， 全球有50万人死亡。预防流感最具成本效益的方法是接种疫苗。 不幸的是，由于每年的抗原变化和漂移，目前的季节性疫苗是无效的。有必要 更好的流感疫苗为了设计出更好的流感疫苗，我们计划使用 由聚合物缩醛化葡聚糖（Ac-DEX）制造的纳米/微米颗粒（MP）。我们之前的数据显示 显示了颗粒降解和针对流感抗原的最佳免疫应答的依赖性。不 只有抗原的释放影响免疫应答，佐剂的释放也是重要的。 佐剂和抗原两者的优化降解与非优化降解相比在存活方面具有急剧变化。 优化配方。我们的粒子系统是独一无二的，因为它依赖于高度可调的聚合物Ac-DEX。 Ac-DEX对于将药剂递送至吞噬细胞是理想的，因为它是酸敏感的并且具有显著的细胞毒性。 在吞噬体的低酸（~pH 5）中的降解增加。除此之外，它还具有可调的降解能力， 速率的范围可以从数小时到数月，这是与常用聚酯（例如， 聚（乳酸-共-乙醇酸）（PLGA）），其具有数月量级的降解。此外，Ac-DEX是独一无二的 因为其降解产物是pH中性的，并且不具有改变局部 pH值或损伤敏感有效载荷。我们有三个具体的目标，探索我们的粒子的各种优化 系统目标1集中于聚合物和颗粒的配制。佐剂的释放速率将为 探讨了将制造具有各种环状缩醛覆盖率的Ac-DEX聚合物，以在宽范围内降解 的时代。在目的2中，我们将评估在表面或表面上负载新流感抗原的效果。 封装在MP中。我们将探索抗原释放的降解速率以及递送途径， 确定提供广泛保护的流感抗原的最佳递送。在目标3中， 探索我们保护雪貂的优化系统。雪貂是流感病毒感染的理想大型动物模型。 使用该模型，我们将评估我们的制剂的疫苗效力，与商业上的疫苗相比， 可用的流感疫苗。

ABSTRACT The WHO estimates there are approximately 5 million cases of influenza infections annually, with approximately 500,000 deaths occurring globally. The most cost-effective protection against influenza is vaccination. Unfortunately, due to yearly antigenic shifts and drifts, current seasonal vaccines are ineffective. There is a need for a better flu vaccine. In order to design a better flu vaccine, we plan on optimizing the immune synapse using nano/microparticles (MPs) fabricated from the polymer acetalated dextran (Ac-DEX). Our previous data has shown a dependence of particle degradation and optimal immune response against an influenza antigen. Not only does the release of the antigen effect the immune response, the release of the adjuvant is also important. The optimized degradation of both adjuvant and antigen has a drastic change in survival compared to non- optimized formulations. Our particle system is unique because it relies on the highly tunable polymer Ac-DEX. Ac-DEX is ideal for delivery of agents to phagocytic cells because it is acid-sensitive and has significantly increased degradation in the low acid (~pH 5) of the phagosome. In addition to this it has tunable degradation rates that can range from hours to months, which is a unique range from commonly used polyesters (e.g. poly(lactic-co-glycolic acid) (PLGA)) that have degradation on the order of months. Moreover, Ac-DEX is unique from polyesters because its degradation products are pH neutral, and do not have the potential to shift the local pH or damage sensitive payloads. We have three specific aims exploring various optimizations of our particle system. Aim 1 is focused on formulation of the polymer and particles. The release rate of the adjuvant will be explored. Ac-DEX polymer with various cyclic acetal coverages will be fabricated to degrade over a broad range of times. In Aim 2 we will evaluate the effect of loading of a novel influenza antigen either on the surface or encapsulated into the MPs. We will explore degradation rates on antigen release as well as delivery routes in determining the optimal delivery of influenza antigens that provide a broad range of protection. In Aim 3 we will explore our optimized system in protecting ferrets. Ferrets are the ideal large animal model for influenza infection. Using this model, we will evaluate the vaccine efficacy of our formulation, in comparison to a commercially available flu vaccine.