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.

Biological Imaging Section Research Technologies Branch NIAID NIH Bethesda Maryland USA

Department of Biochemistry Faculty of Science Charles University Prague Prague Czech Republic

Department of Chemistry University of California Irvine Irvine California USA

Department of Oncology University of Oxford Oxford UK

Imaging Probe Development Center National Heart Lung and Blood Institute NIH Rockville Maryland USA

Institute of Macromolecular Chemistry Academy of Sciences of the Czech Republic Prague Czech Republic

Lymphocyte Biology Section Laboratory of Systems Biology NIAID NIH Bethesda Maryland USA

Vaccine Research Center National Institute of Allergy and Infectious Diseases Bethesda Maryland USA

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Nat Biotechnol. 2015 Nov;33(11):1146-8. doi: 10.1038/nbt.3398. PubMed

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