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

Nature biotechnology (2015-10-27)
Geoffrey M Lynn, Richard Laga, Patricia A Darrah, Andrew S Ishizuka, Alexandra J Balaci, Andrés E Dulcey, Michal Pechar, Robert Pola, Michael Y Gerner, Ayako Yamamoto, Connor R Buechler, Kylie M Quinn, Margery G Smelkinson, Ondrej Vanek, Ryan Cawood, Thomas Hills, Olga Vasalatiy, Kathrin Kastenmüller, Joseph R Francica, Lalisa Stutts, Janine K Tom, Keun Ah Ryu, Aaron P Esser-Kahn, Tomas Etrych, Kerry D Fisher, Leonard W Seymour, Robert A Seder
ABSTRACT

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.

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