Enhanced Humoral Immune Response by High Density TLR Agonist Presentation on Hyperbranched Polymers

Abstract

Prophylactic vaccines often exploit adjuvants to drive potent and directed immune responses. Small-molecule toll-like receptor (TLR) agonists are promising adjuvant candidates; however, the poor pharmacokinetics and rapid distribution of these relatively hydrophilic small molecules results in systemic side effects that have limited their usage to topical application. In this study, TLR7/8 agonists are covalently attached to the highly dense end-groups of hyperbranched polymers synthesized by controlled radical polymerization techniques. Subcutaneous administration of these adjuvants results in a potent and prolonged type I interferon response. When co-administered in a model subunit vaccine, with ovalbumin or the HIV envelope glycoprotein gp120, these hyperbranched polymeric adjuvants potentiate an enhanced immunoglobulin response and near-immediate type-switching to IgG2c, suggesting they promote the type of strong T helper cell 1 immune response that is desirable for the treatment of intracellular pathogens such as mycobacterial and viral infections. Controlling the pharmacokinetics of potent TLR agonists through conjugation to hyperbranched polymers, therefore, enables the development of potent adjuvants in vaccines to drive durable and high-quality humoral immunity.