Enhanced Seasonal Influenza Vaccine Targeting Variable and Conserved Antigens

PROJECT SUMMARY The currently marketed seasonal influenza vaccines have considerable impact on disease, but their efficacy relies on successfully matching the vaccine strains to future circulating virus strains. These vaccines induce neutralizing antibodies primarily against the head region of hemagglutinin and to a lesser extent to neuraminidase. Since these antigens are variable, the vaccines need to be updated regularly. When seasonal influenza vaccines closely match circulating strains, then these vaccines can provide nearly complete protection from infection and disease but if the vaccine strains are poorly matched to circulating strains, vaccine efficacy is severely reduced. Universal influenza vaccines are designed to address this gap by inducing immune responses against antigens that are conserved across seasonal and potentially pandemic strains. These vaccines significantly reduce disease and prevent mortality but generally, do no prevent infection and all disease. We hypothesize that the best efficacy can be obtained by combining the advantages of a closely matched seasonal influenza DNA vaccine with the advantages of a universal influenza DNA vaccine. The seasonal DNA vaccine component can be manufactured closer to influenza seasons to provide a more precise match to circulating strains than currently marketed vaccines. The universal influenza DNA vaccine component would protect from widespread disease and hospitalization if an unexpected, shifted strain with pandemic potential emerged. We also hypothesize that the gene gun is an ideal delivery modality to deliver such DNA vaccines. The GG is needle- free, pain-free, induces protective levels of immunity in humans with 100-1000-fold lower doses than other delivery technologies and notably, induces robust T cell and mucosal immune responses that could increase protection from influenza especially the elderly and immunocompromised that bear the greatest burden of influenza disease and mortality each year. Under Phase I, we will compare a novel doggybone DNA formulation that enables even more rapid and cost-effective manufacture of DNA vaccines to our current plasmid DNA formulation and select a lead formulation. Under phase II, we will compare the lead enhanced seasonal DNA vaccine formulation to an inactivated seasonal influenza vaccine for immunogenicity and efficacy against viruses that are mismatched to the vaccine strain in aged mice as a model for the elderly and in nonhuman primates as a preclinical model that closely mirrors humans. If successful, these studies will result in a new vaccine ready to advance to human clinical trials.