Nanovaccine-Mediated Immune Protection Against Influenza Virus

甲型流感病毒（IAV）是严重呼吸道疾病的主要原因， 发病率和死亡率。该病毒导致大约20万人住院治疗， 在非大流行年份，美国每年有36,000人死亡。鉴于疾病的严重程度， 相关的经济成本和最近在美国出现的新型IAV毒株， 开发新的和有效的“通用”流感疫苗接种策略，以对抗这一新的流感病毒， 严重的全球公共卫生威胁。重要的是，最近的研究强调了免疫接种 其产生局部（即鼻粘膜和肺）组织驻留记忆T和B记忆细胞， 全身免疫提供了最大的保护，以防止未来的IAV遭遇。目前，IAV- 疫苗被设计成在很大程度上诱导IAV特异性抗体，并且通过它们的设计，不诱导肺 在自然IAV感染期间出现的常驻记忆T和B细胞。因此，我们的长期目标是发展一个 一种针对IAV的保护性疫苗，其诱导肺驻留T和B细胞，而不具有 自然感染。为此，我们最近开发了基于纳米颗粒的IAV疫苗（IAV-nanovax）， 模仿，没有与IAV感染相关的病理学，许多被认为是 对于肺驻留T和B细胞诱导和维持是重要的。重要的是这种IAV纳米颗粒疫苗， 打破了冷链，是无针的，并且是生物相容的。这种IAV-nanovax在以下方面显示出有希望的疗效： 对同源和异源IAV感染的保护以及诱导T细胞和B细胞的能力 肺部的反应。因此，本提案将利用以下方面的综合专门知识： 共同PI和共同研究者确定基于纳米颗粒的方法是否允许诱导 持久的IAV特异性肺驻留T和B细胞应答，并在其中提供针对 同源和异源IAV毒株使用以下特定目的：1）确定疫苗 诱导针对同源和异源病毒的最佳免疫和保护的制剂 2）确定诱导针对病毒攻击的最佳保护的疫苗制剂， 远系繁殖的种群。在项目结束时，我们将把我们的发现扩展到与实践相关的领域。 远交种群，建立保护性免疫相关性，可用于评估未来的疗效， 疫苗接种策略，并提供保护性临床前纳米疫苗。

Influenza A virus (IAV) is a major cause of serious respiratory illness and has been responsible for significant morbidity and mortality in humans worldwide. The virus leads to approximately 200,000 hospitalizations and up to 36,000 deaths annually in the United States during non-pandemic years. Given the disease severity, the associated economic costs and the recent appearance of novel IAV strains within the US, there has been a renewed interest in developing novel and efficacious “universal” influenza vaccination strategies to combat this significant global public health threat. Importantly recent studies have highlighted the fact that immunizations that generate local (i.e. nasal mucosa and lung) tissue-resident memory T and B memory cells in addition to systemic immunity offer the greatest protection against future IAV encounters. The currently approved IAV- vaccines are designed to largely induce IAV-specific antibodies, and by their design, do not induce lung resident memory T and B cells that occur during natural IAV infections. Thus our long-term goal is to develop a protective vaccine against IAV that induces lung resident T and B cells without the toxicity that occurs with natural infection. To this end we have recently developed a nanoparticle based IAV vaccine (IAV-nanovax) that mimics, without the pathology associated with IAV infections, many of the key attributes thought to be important for lung resident T and B cell induction and maintenance. Importantly this IAV nanoparticle vaccine, breaks the cold chain, is needle free, and is biocompatible. This IAV-nanovax has shown promising efficacy in protection against homologous and heterologous IAV infections and the ability to induce T cell and B cell responses in the lungs in our preliminary studies. Therefore, this proposal will use the combined expertise of the Co-PIs and Co-Investigators to determine if a nanoparticle-based approach will allow for the induction of durable, IAV-specific, lung-resident T and B cell responses and therein provide robust protection against homologous and heterologous IAV strains using the following Specific Aims: 1) Determine the vaccine formulation that induces optimal immunity and protection against homologous and heterologous virus challenges, 2) Determine the vaccine formulation that induces optimal protection against virus challenge in outbred populations. At the end of the project, we will have extended our findings into translationally relevant outbred populations, established protective immune correlates that can be used to assess the efficacy of future vaccination strategies, and delivered a protective preclinical nanovaccine.