Enhanced Humoral Immune Response by High Density TLR Agonist Presentation on Hyperbranched Polymers (1)
Subunit vaccines are often ineffective in eliciting a satisfactory humoral immune response in the absence of an adjuvant.
A strategy for vaccine adjuvant development is to activate toll‐like receptors (TLR) for immunomodulation of targeted pathways for specific immune profiles. Several TLR agonists with high affinity for TLR7/8 to mimic genetic material in the cytoplasm are attractive for vaccine development to stimulate antigen presenting cells (APCs) and produce cytokines for a specific immune response. The hyperbranched polymer architecture is a promising delivery vehicle for TLR7/8a through its ability to alter the pharmacokinetics to simultaneously reduce systemic toxicity and increase targeted immune activation by introducing a high density of TLR7/8a moieties. Hyperbranched polymers (HBPs) comprising poly(dimethyl‐acrylamide), which has water solubility and biocompatibility, were synthesized by reversible addition fragmentation chain‐transfer (RAFT) polymerization.
The immune activation in response to parabenzylamine analog of R848 (TLR7/8a‐1), HBP‐7/8a‐1, and a HBP negative control was evaluated using TLR7/8 activation resulting in type I interferons (IFN) α production by subcutaneous (SC) or intraperitoneal (IP) injection in C57BL/6 mice. Conjugation of TLR7/8a‐1 to the hyperbranched macromolecular construct extended the duration of IFNα production for both IP and SC administration when compared to R848.
C57BL/6 mice administered with subunit vaccines comprising ovalbumin (Ova) with HBP‐7/8a‐1 adjuvants showed only a modest IgG response, primarily consisting of IgG1.
The high density presentation of TLR7/8 agonists on macromolecular constructs such as HBP‐7/8a promoted a potent cell‐mediated immune response against a co‐presented antigen when compared to the small molecule TLR7/8 agonist itself.