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

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 StuttsJanine K. Tom, Keun Ah Ryu, Aaron P. Esser-Kahn, Tomas Etrych, Kerry D. Fisher, Leonard W. Seymour, Robert A. Seder

Research output: Contribution to journalArticleResearchpeer-review

238 Citations (Scopus)


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.

Original languageEnglish
Pages (from-to)1201-1210
Number of pages10
JournalNature Biotechnology
Issue number11
Publication statusPublished - 1 Nov 2015
Externally publishedYes


  • adjuvants
  • biomedical engineering
  • drug delivery
  • nanoparticles

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