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， 发病率和死亡率。季节性IAV感染导致大约20万 在非大流行年份，美国每年有36，000人住院和死亡。而且 1918年（全世界约5000万人死亡）、1957-58年（全世界约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。近期出现 高致病性H5 N2病毒和欧亚高致病性禽流感H5病毒在美国以及高 在感染大流行前禽流感H5 N1病毒的人类中观察到的死亡率（死亡率约为55-60%） 引起了高度关注因此，人们重新对开发新颖有效的药物感兴趣。 流感疫苗接种策略，提供广泛的保护，以应对这一重大的全球公众 健康和流行病威胁。最近的研究已经重要地表明，诱导局部（即鼻）免疫应答的策略是有效的。 粘膜和肺）组织驻留记忆T和B记忆细胞除了系统免疫外， 最大的保护，防止未来异源IAV的遭遇。目前已获得许可的IAV疫苗， 设计不诱导肺驻留记忆T和B细胞应答。因此，我们的长期目标是发展一个 诱导肺和鼻驻留T和B细胞的抗大流行前禽IAV的保护性通用疫苗 还有全身免疫我们已经开发了一种基于聚酸酐纳米颗粒的IAV疫苗（IAV- nanovax）对抗季节性IAV，其打破冷链，是无针的，并且是生物相容的。这个IAV- nanovax已显示出对同源和异源季节性IAV感染的保护功效， 在肺和鼻道中诱导T细胞和B细胞应答的能力。H5 IAV的HA是 被认为免疫原性差，并且当与来自 季节性IAV，从而限制了疫苗设计。重要的是，我们先前对聚酸酐纳米颗粒的研究 还表明，即使在抗原的正常次优水平下，它们也能诱导强免疫。因此本 提案将利用PI和合作研究者的综合专业知识以及稳健的临床前模型， 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，肺部驻留的T细胞， 和B细胞应答以及针对同源和异源大流行前禽流感的广泛保护 1）确定禽流感大流行前IAV-nanovax在IAV毒株中的效力， 诱导强有力的局部和全身免疫并赋予针对随后的H5 IAV暴露的保护， 2)确定apIAV-nanovax是否具有广泛的保护作用。

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.