Vaccine Strategies for Preventing Pandemic Influenza Viruses

The development of a universal influenza vaccine that would provide long-lasting protection against divergent strains has been a high-priority for many years. Some strategies have shown promise and very real improvements in the overall breadth of protection. For example, consensus vaccines have shown improvement over wildtype immunogens. Another interesting strategy focuses on driving stalk-directed immunity against influenza, especially since the HA2 stalk domain is indisputably much more conserved than the HA1 head domain. Approaches such as stabilized HA2 stalk immunogens, stalk-ferritin fusion viral particles, or chimeric stalk domains fused to irrelevant avian HA1 head domains were used to drive stalk-directed immunity. Additionally, the strategy of sequential immunization with variable irrelevant HA1 head domains, specifically amplified anti-stalk immunity and increased the breadth of immunity against divergent influenza virus strains. These stalk immunogens have been delivered using recombinant proteins, viral vectors, and, more recently, mRNA-lipid nanoparticles (LNPs). Ironically, most of these strategies employ a single monovalent immunogen, which is counterintuitive to the multivalent trivalent and quadrivalent vaccine strategies that have shown significant improvement in vaccine design. A novel Epigraph strategy that uses a computationally-optimized trivalent immunogen has shown broad cross-protective immunity. Experiments in mice, ferrets, and swine have shown this Epigraph vaccine strategy to be superior to wildtype immunogens and commercial vaccines. We propose to combine the strengths of five of these approaches to create a more universal vaccine immunogen than when applied individually. This application describes an influenza vaccine that combines the immunodominant HA1 heads of Epigraph (1) genes with the conserved HA2 stalk of consensus (2) immunogens to create novel multivalent chimeric (3) optimized (ECChO) immunogens. We will use a sequential prime- boost/boost immunization strategy (4) that has shown optimal and maximized immunity to amplify stalk-directed immunity. Finally, we will deliver the multivalent vaccine using recombinant Adenoviral viral vectors (rAd) and/or mRNA-LNP delivery systems (5). This vaccine approach will be investigated for efficacy against H2N2, H5N1, H7N9, and H9N2 influenza viruses as all of these avian influenza viruses are actively detected in the U.S. and there is an ongoing endemic of avian H5 infections in cattle, poultry and humans. In addition, H7N9 and H9N2 human infections result in severe respiratory illness and death in approximately 40% of hospitalized cases. All of these avian influenza viruses have significant disastrous pandemic potential. Project Number: 1R01AI191514-01A1 | Fiscal Year: 2026 | NIH Institute/Center: National Institute of Allergy and Infectious Diseases (NIAID) | Principal Investigator: ERIC WEAVER (+1 co-PI) | Institution: UNIVERSITY OF NEBRASKA LINCOLN, LINCOLN, NE | Award Amount: $799,792 | Activity Code: R01 | Study Section: Special Emphasis Panel[ZRG1 DCAI-N (88)] View on NIH RePORTER: https://reporter.nih.gov/project-details/1R01AI19151401A1