In vivo characterization of the physicochemical properties of polymer-linked TLR agonists that enhance vaccine immunogenicity.
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.