Novel lipid A mimetics, BECC438 and BECC470, act as potent adjuvants in bacterial and viral subunit vaccines

Abstract

Abstract Infectious diseases continue to be the leading cause of morbidity and mortality worldwide, an urgent need exists to develop effective vaccines against a variety of pathogens. Effective vaccines contain target pathogen antigens and adjuvant(s) which effect the magnitude, duration and mechanism of action of the immune response. Bacterial enzyme combinatorial chemistry (BECC) was developed to synthesize custom bacterial lipid A that are partial agonists for innate immune receptor Toll-like receptor 4 (TLR4). BECC is a robust mechanism for design of lipid A mimetics that drive specific activating immunity while avoiding excessive adverse host reactions. Initial screenings identify two lead adjuvant candidates, BECC438 and BECC470, that are formulated with bacterial and viral antigens, including Yersinia pestis (rF1-V), Staphlococcus alpha toxin, and HPV (VLPs). Mice are immunized on two-week intervals with several squalene or aqueous based BECC formulations. Antigen-specific serum antibody titers measured by ELISA for total IgG, IgG1, and IgG2c(2a) for BECC formulations are significantly more balanced than those currently approved for clinical use. Pathogen challenge models also show increased levels of efficacy/survival. Both BECC compounds allow for durable antibody production, antigen sparing, dose sparing, adjuvant sparing, production of T follicular helper cells, and provide protection against a heterologous challenge in viral infection models. Additionally, BECC adjuvanted vaccines with the model antigen ovalbumin show balanced and durable antibody responses in multiple murine backgrounds C57BL6, BALBc, and CD-1. BECC molecules are effective components of next-generation infectious disease vaccines.