Protection and Immunity after Polyanhydride Nanoparticle Vaccination against Avian Influenza A 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。季节性IAV感染导致约20万人 在非大流行年份，美国每年的住院人数和36,000人死亡。此外， 1918年(全球约5000万人死亡)、1957-58年(全球约100万人死亡)和1968-69年的IAV大流行 (全世界约70万人死亡)进一步证明了IAV对人类健康的影响。最近的亮相 美国高致病性H5N2和欧亚高致病性禽流感H5病毒以及高致病性 在感染大流行前禽流感H5N1病毒的人中观察到的死亡率(死亡率约为55-60%) 加剧了人们的担忧。因此，人们对开发新奇和有效的产品重新产生了兴趣 流感疫苗接种战略，提供广泛的保护，以对抗这一重要的全球公众 健康和大流行威胁。最近的研究重要地表明，诱导局部(即鼻腔)的策略 粘膜和肺)组织驻留记忆T和B记忆细胞除了系统免疫外，还提供 对未来异种IAV遭遇的最大保护。目前获得许可的IAV疫苗按其 设计不会诱导肺部常驻记忆T细胞和B细胞反应。因此，我们的长期目标是发展一种 大流行前禽流感病毒诱导肺和鼻腔内T、B细胞的保护性通用疫苗 除了全身免疫力之外。我们开发了一种以聚酸酐纳米颗粒为基础的IAV疫苗(IAV- 抗季节性IAV，打破冷链，无针刺，并具有生物相容性。这个IAV- Nanovax在预防同源和异源季节性IAV感染方面显示出有效性，并 在肺部和鼻腔中诱导T细胞和B细胞反应的能力。来自H5 IAV的HAD是 被认为免疫原性差，与HAS相比需要更高的剂量才能有效 季节性IAV从而限制了疫苗设计。关键的是，我们之前在聚酸酐纳米颗粒方面的工作 还表明，即使在正常情况下抗原水平不佳的情况下，它们也可以诱导强大的免疫。因此，这 提案将使用PI和协查人员的组合专业知识以及强大的临床前模型来 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细胞 B细胞反应和对同源和异源大流行前禽类的广泛保护 使用以下特定目的的IAV株：1)确定禽流感大流行前的IAV-Nanovax对 诱导强大的局部和系统免疫，并对随后的H5IAV暴露提供保护， 2)确定apIAV-Nanovax是否提供广泛的保护。

Influenza A virus (IAV) is a major cause of serious respiratory illness and has been responsible for significant morbidity and mortality in humans worldwide. Seasonal IAV infections lead to approximately 200,000 hospitalizations and 36,000 deaths annually in the United States during non-pandemic years. Furthermore, the IAV pandemics of 1918 (~50 million deaths worldwide), 1957-58 (~1 million deaths worldwide) and 1968-69 (~700,000 deaths worldwide) further demonstrate the impact of IAV on human health. The recent appearance of highly pathogenic H5N2 and the Eurasian highly pathogenic avian H5 viruses in the US as well as the high mortality rate observed in humans infected with the pre-pandemic avian H5N1 (~55-60% mortality rate) IAVs has heightened concerns. Thus, there has been a renewed interest in developing novel and efficacious influenza vaccination strategies that confer broad based protection to combat this significant global public health and pandemic threat. Recent studies have importantly shown that strategies that induce 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 heterologous IAV encounters. The currently licensed IAV-vaccines by their design do not induce lung resident memory T and B cell responses. Thus, our long-term goal is to develop a protective universal vaccine against pre-pandemic avian IAV that induces lung and nasal resident T and B cells in addition to systemic immunity. We have developed a polyanhydride nanoparticle based IAV vaccine (IAV- nanovax) against seasonal IAV that breaks the cold chain, is needle free, and is biocompatible. This IAV- nanovax has shown efficacy in protection against homologous and heterologous seasonal IAV infections and the ability to induce T cell and B cell responses in the lungs and nasal passages. The HAs from H5 IAV are thought to be poorly immunogenic and require higher doses to be effective when compared to HAs from seasonal IAV thereby limiting vaccine design. Critically, our prior work with polyanhydride nanoparticles has also shown that they can induce robust immunity even at normally suboptimal levels of antigen. Therefore, this proposal will use the combined expertise of the PI and Co-Investigators and robust pre-clinical models to determine if a nanoparticle-based approach will allow for the induction of durable, IAV-specific, lung-resident T and B cell responses and broad-based protection against homologous and heterologous pre-pandemic avian IAV strains using the following Specific Aims: 1) Determine the efficacy of avian pre-pandemic IAV-nanovax in inducing robust local and systemic immunity and conferring protection against subsequent H5 IAV exposures, 2) Determine if apIAV-nanovax confers broad-based protection.