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，并已导致重大 世界各地人类的发病率和死亡率。该病毒导致大约20万人住院治疗，甚至更多 在非大流行年，美国每年有36,000人死亡。考虑到疾病的严重性， 相关的经济成本和最近在美国出现的新型IAV毒株，已经出现了 人们对开发新的、有效的“通用”流感疫苗接种战略重新产生了兴趣，以应对这一问题 严重的全球公共卫生威胁。重要的是，最近的研究强调了这样一个事实，即免疫接种 除了产生局部(即鼻黏膜和肺)组织驻留记忆T和B记忆细胞外 系统免疫力提供了最大的保护，防止未来的IAV遭遇。目前批准的IAV- 疫苗被设计成在很大程度上诱导IAV特异性抗体，而按照他们的设计，不会诱导肺 在自然感染IAV期间发生的常驻记忆T和B细胞。因此，我们的长期目标是开发一种 针对IAV的保护性疫苗，可诱导肺内常驻T和B细胞，而不会产生与 自然感染。为此，我们最近开发了一种基于纳米颗粒的IAV疫苗(IAV-Nanovax)，该疫苗 模拟，没有与IAV感染相关的病理，许多关键特征被认为是 对肺部常住T、B细胞的诱导和维持很重要。重要的是这种IAV纳米疫苗， 打破了冷链，是无针的，是生物兼容的。这种IAV-Nanovax在 对同种和异种IAV感染的保护作用及诱导T细胞和B细胞的能力 在我们的初步研究中，肺部的反应。因此，这项提案将使用 联合PIs和联合调查员以确定基于纳米颗粒的方法是否允许诱导 持久的、IAV特异性的、驻留在肺内的T和B细胞反应，其中提供了强大的保护作用 使用以下特定目的的同源和异源IAV毒株：1)确定疫苗 诱导最佳免疫力和对同源和异种病毒的保护的配方 挑战，2)确定可针对病毒挑战提供最佳保护的疫苗配方 远亲繁殖的种群。在项目结束时，我们将把我们的发现扩展到与翻译相关的领域 远交种群，已建立的保护性免疫相关性，可用于评估未来的疗效 疫苗接种策略，并提供了保护性的临床前纳米疫苗。

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.