A TLR7 Agonist Conjugated to a Nanofibrous Peptide Hydrogel as a Potent Vaccine Adjuvant

Abstract Toll‐like receptors (TLRs) recognize pathogen‐ and damage‐associated molecular patterns and, in turn, trigger the release of cytokines and other immunostimulatory molecules. As a result, TLR agonists are increasingly being investigated as vaccine adjuvants. Many of these agonists are small molecules that quickly diffuse away from the vaccination site, limiting their co‐localization with antigens and, thus, their effect. Here, the small‐molecule TLR7 agonist 1V209 is conjugated to a positively‐charged multidomain peptide (MDP) hydrogel, K 2 , which was previously shown to act as an adjuvant promoting humoral immunity. Mixing the 1V209‐conjugated K 2 50:50 with the unfunctionalized K 2 produces hydrogels that retain the shear‐thinning and self‐healing physical properties of the original MDP while improving the solubility of 1V209 more than 200‐fold compared to the unconjugated molecule. When co‐delivered with ovalbumin as a model antigen, 1V209‐functionalized K 2 produces a robust Th2 immune response and an antigen‐specific Th1 immune response superior to alum, a widely used vaccine adjuvant. Together, these results suggest that K 2 MDP hydrogels functionalized with 1V209 are a promising adjuvant for vaccines against infectious diseases, especially those benefiting from a combined Th1 and Th2 immune response.