Lynn, GM; Laga, R; Darrah, PA; Ishizuka, AS; Balaci, AJ; Dulcey, AE; Pechar, M; Pola, R; Gerner, MY; Yamamoto, A; Buechler, CR; Quinn, KM; Smelkinson, MG; Vanek, O; Cawood, R; Hills, T; Vasalatiy, O; Kastenmüller, K; Francica, JR; Stutts, L; Tom, JK; Ryu, KA; Esser-Kahn, AP; Etrych, T; Fisher, KD; Seymour, LW; Seder, RA
The efficacy of vaccine adjuvants such as Toll-like receptor agonists (TLRa) can be improved through formulation and delivery approaches. Here, we attached small molecule TLR-7/8a to polymer scaffolds (polymer-TLR-7/8a) and evaluated how different physicochemical properties of the TLR-7/8a and polymer carrier influenced the location, magnitude and duration of innate immune activation in vivo. Particle formation by polymer-TLR-7/8a was the most important factor for restricting adjuvant distribution and prolonging activity in draining lymph nodes. The improved pharmacokinetic profile by particulate polymer-TLR-7/8a was also associated with reduced morbidity and enhanced vaccine immunogenicity for inducing antibodies and T cell immunity. We extended these findings to the development of a modular approach in which protein antigens are site-specifically linked to temperature-responsive polymer-TLR-7/8a adjuvants that self-assemble into immunogenic particles at physiologic temperatures in vivo. Our findings provide a chemical and structural basis for optimizing adjuvant design to elicit broad-based antibody and T cell responses with protein antigens.