Influenza vaccines using liposomal formulations of toll-like receptor (TLR) 7/8 and 4 agonists as adjuvants

Abstract

Abstract Influenza virus infection is a global health concern and causes severe illness and thousands of deaths each year. While there are currently licensed vaccines available for both seasonal and pandemic influenza viruses there are several issues to consider; 1) current vaccines do not provide supra-seasonal or universal protection against influenza subtypes, 2) antigenic mismatch between the vaccine and circulating influenza strains impact vaccine efficacy, 3) and the efficacy of influenza seasonal vaccines could be improved in the elderly and immune compromised populations. Therefore, vaccine adjuvants capable of inducing more robust and broadly cross-protective immune responses to various subtypes of influenza virus is a critical unmet need. To address this challenge, we developed a synthetic dual TLR adjuvant combination system (TRAC-478) to improve influenza vaccine immunity. Preliminary data in human peripheral blood mononuclear cells demonstrate that combining our synthetic TLR7/8 and TLR4 agonists results in a synergistic innate immune responses. Influenza vaccine immunogenicity studies in both murine and pig models demonstrate the safety and efficacy of this new dual TLR adjuvant system. Using a co-encapsulated TRAC-478 liposome delivery system with a split-flu vaccine resulted in strong anti-influenza humoral, Th1 cell mediated immunity, and protection from a heterologous influenza challenge in mice. We hypothesize that using the TRAC-478 adjuvant system in combination with current influenza vaccines will induce a more robust and broadly cross-protective immune responses to circulating or pandemic influenza virus.