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: 10328236
• 负责人: Kristy M Ainslie
• 金额: $ 56.87万
• 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/10328236
• 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 infection; 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 efficacy; vaccine evaluation; vaccine formulation

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 世界卫生组织估计每年约有 500 万例流感感染病例，其中约 全球有 50 万人死亡。预防流感最经济有效的方法是接种疫苗。 不幸的是，由于每年的抗原变化和漂移，目前的季节性疫苗无效。有需要 以获得更好的流感疫苗。为了设计更好的流感疫苗，我们计划使用优化免疫突触 由聚合物乙酰化葡聚糖 (Ac-DEX) 制成的纳米/微粒 (MP)。我们之前的数据有 显示了颗粒降解和针对流感抗原的最佳免疫反应的依赖性。不是 仅抗原的释放影响免疫反应，佐剂的释放也很重要。 与非佐剂和抗原的优化降解相比，存活率发生了巨大变化。 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 是向吞噬细胞递送药剂的理想选择，因为它对酸敏感并且具有显着的 吞噬体在低酸（~pH 5）下降解增加。除此之外，它还具有可调节的衰减 速率范围从几小时到几个月不等，这是与常用聚酯（例如聚酯纤维）不同的独特范围。 聚（乳酸-乙醇酸）（PLGA））的降解时间约为数月。此外，Ac-DEX 是独一无二的 来自聚酯，因为其降解产物的 pH 值为中性，并且没有可能改变局部 pH 值或损坏敏感有效负载。我们有三个具体目标来探索粒子的各种优化 系统。目标 1 侧重于聚合物和颗粒的配方。佐剂的释放速率为 探索过。具有各种环状缩醛覆盖度的 Ac-DEX 聚合物将被制造成在广泛的范围内降解 次。在目标 2 中，我们将评估新型流感抗原负载在表面或表面上的效果。 封装到 MP 中。我们将探索抗原释放的降解率以及递送途径 确定提供广泛保护的流感抗原的最佳递送方式。在目标 3 中，我们将 探索我们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。 使用该模型，我们将评估我们配方的疫苗功效，并与商业疫苗进行比较 可用的流感疫苗。