Optimizing a Universal Influenza Subunit Nano/Microparticulate Vaccine

优化通用流感亚单位纳米/微粒疫苗

• 批准号: 9916920
• 负责人: Kristy M Ainslie
• 金额: $ 60.43万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-01-15 至 2024-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9916920
• 关键词: Acetals; Acids; Address; Adjuvant; Affect; Agonist; Algorithms; Animal Model; Animals; Anthrax disease; Antibody Response; Antigen Presentation; Antigens; Antiviral Agents; Avian Influenza; B-Cell Activation; Biopolymers; Birds; CD4 Positive T Lymphocytes; Cells; Centers for Disease Control and Prevention (U.S.); Cessation of life; Consensus; Cytosol; Data; Dependence; Dextrans; Dose; Drug Delivery Systems; Emergency Situation; Emulsions; Encapsulated; Endotoxins; Evaluation; FDA approved; Ferrets; Formulation; Genetic Drift; Glycolates; Goals; Hemagglutinin; Hour; Human; Immune; Immune response; Individual; Infection; Infection prevention; Influenza; Influenza A Virus, H1N1 Subtype; Influenza A virus; Intramuscular; Lead; Methodology; Modeling; Mus; Mutation; Neuraminidase; Nose; Pathogenesis; Pathogenicity; Pathology; Periodicity; Phagocytes; Phagosomes; Plague; Polyesters; Polymers; Population; Protein Denaturation; Protein Subunits; Route; Schedule; Shapes; Stimulator of Interferon Genes; Subunit Vaccines; Surface; System; Testing; Time; Toxic effect; Vaccinated; Vaccination; Vaccines; Viral Load result; Virus Diseases; aluminum sulfate; computer generated; controlled release; cost effective; design; flu; head-to-head comparison; immunological synapse; improved; influenza virus vaccine; influenzavirus; innovation; mouse model; nano; nanoparticle; novel; pandemic disease; pandemic influenza; particle; prevent; process optimization; protective efficacy; receptor; response; vaccine delivery; vaccine development; vaccine efficacy

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.

抽象的 世卫组织估计每年大约有500万例流感感染病例 全球500,000人死亡。针对流感的最具成本效益的保护是疫苗接种。 不幸的是，由于每年的抗原转移和漂移，目前的季节性疫苗无效。有需要 为了获得更好的流感疫苗。为了设计更好的流感疫苗，我们计划使用 纳米/微粒（MPS）是由聚合物乙酰化葡萄糖（AC-DEX）制造的。我们以前的数据有 显示颗粒降解和最佳免疫反应对流感抗原的依赖性。不是 仅释放抗原效应免疫反应，佐剂的释放也很重要。 辅助和抗原的优化降解与非 - 优化的配方。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非常适合向吞噬细胞递送剂，因为它具有酸敏感，并且具有显着的 吞噬体的低酸（〜pH 5）降解增加。除此之外，它还具有可调的降解 从小时到几个月的速率，这是一个独特的范围，从常用的聚酯（例如 在几个月内降解的聚（乳酸 - 乙醇酸））。而且，AC-DEX是独一无二的 从polyesters出发，因为它的降解产物是pH中性的，并且没有可能移动局部的潜力 pH或伤害敏感有效载荷。我们有三个特定的目的探索粒子的各种优化 系统。 AIM 1专注于聚合物和颗粒的配方。佐剂的释放率将是 探索。将制造具有各种环状乙酰覆盖范围的AC-DEX聚合物，以在广泛的范围内降解 时间。在AIM 2中，我们将评估新型流感抗原在表面或 封装在国会议员中。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。在目标3中，我们将 探索我们在保护雪貂的优化系统。雪貂是流感感染的理想大型动物模型。 使用此模型，我们将与商业上的配方疫苗功效进行评估 可用的流感疫苗。