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

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 polym...

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Bibliographic Details
Published in:Nature biotechnology 2015-11, Vol.33 (11), p.1201-1210
Main Authors: Lynn, Geoffrey M, Laga, Richard, Darrah, Patricia A, Ishizuka, Andrew S, Balaci, Alexandra J, Dulcey, Andrés E, Pechar, Michal, Pola, Robert, Gerner, Michael Y, Yamamoto, Ayako, Buechler, Connor R, Quinn, Kylie M, Smelkinson, Margery G, Vanek, Ondrej, Cawood, Ryan, Hills, Thomas, Vasalatiy, Olga, Kastenmüller, Kathrin, Francica, Joseph R, Stutts, Lalisa, Tom, Janine K, Ryu, Keun Ah, Esser-Kahn, Aaron P, Etrych, Tomas, Fisher, Kerry D, Seymour, Leonard W, Seder, Robert A
Format: Article
Language:English
Subjects:
Adjuvants, Immunologic - chemistry
Animals
Antigens
Drug Carriers - chemistry
Drug delivery systems
Female
Male
Mice
Mice, Inbred C57BL
Nanoparticles
Polymers
T-Lymphocytes - immunology
Toll-like receptors
Toll-Like Receptors - agonists
Vaccines
Vaccines - immunology
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Summary: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.
ISSN:1087-0156
1546-1696
DOI:10.1038/nbt.3371