R-DOTAP adjuvant formulation for bivalent COBRA H1/H3 vaccines: characterization and optimization

Abstract In the previous CIVIC (Collaborative Influenza Vaccine Innovation Centers) option period, we tested enantiomerically pure R-DOTAP cationic lipid nanoparticles as an adjuvant to promote an immune response to recombinant COBRA antigens. In that contract, we showed R-DOTAP could be formulated with recombinant COBRA antigens to induce robust cellular and antibody responses and protect mice from influenza challenge. In this proposal, we propose to characterize the vaccine formulation containing R-DOTAP adjuvant and the influenza antigens, including recombinant COBRA antigens and influenza HA used in commercial vaccines (Flublok and Fluzone. We will perform studies to evaluate the antigen-adjuvant interactions, the effect of salt and excipients in the vaccine formulation, and the stability of the vaccine formulation. These testing activities will assess the value of R-DOTAP in adjuvating influenza vaccines. RDOTAP is designed to spontaneously form ~100 nm nanoparticles in an aqueous suspension to promote effective dendritic cell uptake. Its unique properties stimulate excellent antibody and CD8+ T cell responses to combined antigens by activating type I IFN without adding cytokines or TLR agonists (9). R-DOTAP has successfully been tested in a phase I human clinical trial as part of an HPV16 therapeutic vaccine (PDS0101), and confirmed to facilitate antigen cross-presentation and induction of strong antigen-specific CD8+ T-cell responses as well as memory T-cell responses against the viral target, associated with regression of disease and without systemic toxicity. This project aims to generate data needed to support human testing of the investigational vaccine. Our collaborator has stocks of cGMP clinical grade R-DOTAP nanoparticles vialed in anticipation of phase II clinical trials. Thus, the proposed vaccine can be rapidly produced and deployed for human testing.