Optimizing a Universal Influenza Subunit Nano/Microparticulate Vaccine

摘要 世卫组织估计，每年约有500万流感感染病例，其中约 全球正在发生50万起死亡事件。预防流感最具成本效益的预防措施是接种疫苗。 不幸的是，由于抗原每年的变化和漂移，目前的季节性疫苗无效。有必要 为了更好的流感疫苗。为了设计出更好的流感疫苗，我们计划使用 由聚合物缩醛葡聚糖(Ac-DEX)制备的纳米/微米粒子(MPS)。我们之前的数据显示 表现出对颗粒降解的依赖性和对流感抗原的最佳免疫反应。不 只有抗原的释放才会影响免疫反应，佐剂的释放也很重要。 佐剂和抗原的优化降解与未降解的相比存活率发生了巨大的变化 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是将药物输送到吞噬细胞的理想药物，因为它对酸敏感，并且具有显著的 吞噬小体在低酸度(~pH 5)时降解增加。除此之外，它还具有可调的降级 价格从几小时到几个月不等，这是与常用聚酯(例如 聚乳酸-羟基乙酸(PLGA))的降解率约为几个月。此外，Ac-DEX是独一无二的 来自聚酯，因为它的降解产物是pH中性的，并且不会改变局部 PH值或对损坏敏感的有效载荷。我们有三个具体目标来探索我们的粒子的各种优化 系统。目标1集中在聚合物和颗粒的配方上。佐剂的释放率为 探索过了。具有不同环缩醛覆盖物的AC-DEX聚合物将被制造成在广泛的范围内降解 很多次了。在目标2中，我们将评估一种新的流感抗原负载在表面或 被封装到MPS中。我们将探索抗原释放的降解率以及在 确定提供广泛保护的流感抗原的最佳输送方式。在《目标3》中，我们将 探索我们在保护雪貂方面的优化系统。雪貂是流感感染的理想大型动物模型。 使用这个模型，我们将评估我们配方的疫苗效力，并与商业疫苗进行比较。 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.