Journal
NATURE BIOTECHNOLOGY
Volume 33, Issue 11, Pages 1201-+Publisher
NATURE RESEARCH
DOI: 10.1038/nbt.3371
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Funding
- BIOPOL project (Ministry of Education, Youth and Sports of the Czech Republic) [EE2.3.30.0029]
- Czech Science Foundation [15-15181S]
- Charles University [UNCE 204025/2012]
- Cancer Research UK [C552/A17720]
- Office of AIDS Research of the US National Institutes of Health
- National Institute of Allergy and Infectious Diseases of the US National Institutes of Health
- Cancer Research UK [17720] Funding Source: researchfish
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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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