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.
