Abstract
Vaccine design has undergone a shift towards the use of purified protein subunit vaccines, which offer increased safety and greater control over antigen specificity, but at the expense of immunogenicity. Here we report the development of a new polymer-based vaccine delivery platform engineered to enhance immunity through the co-delivery of protein antigens and the Toll-like receptor 7 (TLR7) agonist imiquimod (IMQ). Owing to the preferential solubility of IMQ in fatty acids, a series of block copolymer micelles with a fatty acid-mimetic core comprising lauryl methacrylate (LMA) and methacrylic acid (MAA), and a poly(ethylene glycol) methyl ether methacrylate (PEGMA) corona decorated with pyridyl disulfide ethyl methacrylate (PDSM) moieties for antigen conjugation were synthesized via reversible addition-fragmentation chain transfer (RAFT) polymerization. Carriers composed of 50 mole% LMA (LMA50) demonstrated the highest IMQ loading (2.2 w/w%) and significantly enhanced the immunostimulatory capacity of IMQ to induce dendritic cell maturation and proinflammatory cytokine production. Conjugation of a model antigen, ovalbumin (OVA), to the corona of IMQ-loaded LMA50 micelles enhanced in vitro antigen uptake and cross-presentation on MHC class I (MHC-I). A single intranasal (IN) immunization of mice with carriers co-loaded with IMQ and OVA elicited significantly higher pulmonary and systemic CD8+ T cell responses and increased serum IgG titer relative to a soluble formulation of antigen and adjuvant. Collectively, these data demonstrate that rationally designed fatty acid-mimetic micelles enhance intracellular antigen and IMQ delivery and have potential as synthetic vectors for enhancing the immunogenicity of subunit vaccines.