Improved Delivery of a Broadly Active Influenza Subunit Vaccine

Influenza is a major burden every season causing up to 9,000,000 illnesses in the United States. Vaccines are available; however, their efficacy is limited. Antigenic drift/shift of the virus means that the vaccine must be redesigned every year to incorporate new circulating strains, and predictions for what the major circulating strains will be are not always correct leading to incomplete protection. To subvert the mutating virus, computationally optimized broadly reactive antigen (COBRA) hemagglutinin (HA) immunogens have been created that induce a broadly neutralizing antibody response; however, the immunogenicity of a COBRA subunit vaccine is limited but can be improved by delivery strategies that can enhance targeting to immune cells and act as adjuvants to activate the immune system. The work presented herein aims to improve the efficacy of a COBRA HA vaccine using drug delivery platforms. First, polymeric microparticles (MPs) composed of acetalated dextran (Ace-DEX) encapsulating COBRA HA and a STING agonist are investigated. Mice vaccinated with these MPs showed a broadly active humoral response, an improved cellular response when compared to an FDA-approved vaccine adjuvant, protection after lethal influenza challenge, and storage stability outside the cold chain. The efficacy of this platform was also assessed in immunocompromised mouse models such as obesity, aging, and chemotherapy-induced immunosuppression. Next, a coordination polymer is used to deliver COBRA HA along with aTLR agonist. Again, this platform shows efficacy in vivo as evidenced by a strong cellular and humoral response, protection after a lethal influenza challenge, and stability outside the cold chain. Finally, the efficacy of lipid nanoparticles as a carrier for mRNA encoding COBRA was evaluated, and an in vivo efficacy study showed that the adjuvant containing MPs decreased the humoral response to the COBRA HA LNPs. Overall, in the development of a broadly active influenza vaccine it is important to consider multiple delivery platforms. The work described herein shows that each platform has its own set of advantages and disadvantages. Together this work will aid in the selection of the most efficacious platform for a broadly active influenza vaccine that will help to reduce the major yearly burden of influenza.Doctor of Philosoph