Monday, May 19, 2025
5/19/2025
Universal room temperature stable influenza nanovaccine - PROJECT SUMMARY / ABSTRACT 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 36,000 deaths annually in the U.S. during non-pandemic years. Given the disease severity, the associated economic costs and the recent appearance of novel IAV strains and/or variants, there is an urgent need to develop novel and efficacious “universal” vaccines to combat this significant global public health threat. Current IAV vaccines are limited by the need to account for viral antigen drift/shift, the slow manufacturing process, low to moderate efficacy rates, and the inability to induce lung resident memory T and B cells that occur during natural IAV infections. The most efficacious universal vaccine may need to target conserved epitopes within both the head and the stem regions of the IAV hemagglutinin (HA) and include conserved proteins that drive T cell immunity. Immunizations that generate local tissue-resident memory T and B memory cells and systemic immunity offer the greatest protection against future IAV encounters. Thus, our long-term goal is to develop a universal IAV vaccine that will induce broadly neutralizing antibodies (bnAb) and durable, IAV-specific, lung- resident T and B cell immunity, protect against group 1 and 2 IAV strains, and not require a cold chain. To this end, we have discovered a novel immunogen based on equine recombinant HA3 (rHA3) that elicits Ab in multiple species and protects across influenza groups by targeting both the HA head and stem regions. We have also developed two promising polymeric nanovaccine platforms that have been shown to increase Ab titer, improve T cell immunity, and prolong antigen release after vaccination. One is comprised of biodegradable polyanhydride nanoparticles and the other is based on pentablock copolymer micelles. We have shown that both platforms induced protective immunity with reduced viral load upon vaccination. The IAV nanovaccine showed promising efficacy in protection against homologous and heterologous IAV infections and induced T and B cell responses in the lungs. This proposal will use the combined expertise of our team to determine if a nanovaccine approach will induce both bnAb and durable, lung-resident T and B cell immunity and lead to universal protection using the following specific aims: 1) synthesize and characterize rHA3 nanovaccines;; 2) establish the safety and toxicological profile of rHA3 nanovaccine in mice and ferrets;; 3) determine rHA3 nanovaccine formulation(s) that will elicit the most appropriate and sustained response to IAV following a single-dose vaccination;; 4) design multivalent rHA3 nanovaccines that increase bnAb and CMI to diverse strains of IAV;; and 5) develop GLP-compliant process for synthesis of identified lead universal nanovaccine and evaluate its shelf life in delivery devices. The proposed studies with tightly bound milestones and decision points will lead to a final product that will meet NIAID’s characterization of a protective universal IAV vaccine and provide important first steps for translating our findings to human clinical trials.
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