Modulation of the Adjuvant Potential of Imidazoquinoline-Based TLR7/8 Agonists via Alum Adsorption

Toll-like receptor (TLR)-7/8 agonists are promising candidates for the development of new-generation vaccine adjuvants. Adsorption of TLR7/8 agonists on aluminum salts (alum) may further enhance vaccine immunogenicity. Evaluation of the adjuvanticity of the most active dual TLR7/8 agonists, 1-(3-(aminomethyl)benzyl)-2-butyl-1H-imidazo[4,5-c]quinolin-4-amine (m-AM-BBIQ, 10) and its para derivative p-AM-BBIQ (11), along with their gallic acid and protocatechuic acid amides in a recombinant-protein-based COVID-19 vaccine platform confirmed the importance of vic-polyphenolic functionality in TLR7/8 agonists for the alum adsorption, thereby resulting in a balanced Th1/Th2 immune response. A novel 7,8-dihydroxy-IMDQ derivative (dh-p-AM-BBIQ, 21) was designed wherein the vic-diphenolic functionality was introduced in the quinoline ring of the imidazo[4,5-c]quinoline scaffold. Compound 21 not only retained the TLR7 agonistic activity (EC₅₀ = 3.72 μM) but also showed high adsorption to alum and induced a potent antibody response to SARS-CoV-2 spike protein and hepatitis B surface antigen immunized mice. The combination adjuvant comprising compound 21 adsorbed to alum represents a promising candidate for further development as a human and veterinary vaccine adjuvant.