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Nat Biotechnol. 2015 Nov;33(11):1201-10. doi: 10.1038/nbt.3371. Epub 2015 Oct 26.

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

Author information

1
Vaccine Research Center, National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), Bethesda, Maryland, USA.
2
Department of Oncology, University of Oxford, Oxford, UK.
3
Institute of Macromolecular Chemistry, Academy of Sciences of the Czech Republic, Prague, Czech Republic.
4
Imaging Probe Development Center, National Heart, Lung, and Blood Institute, NIH, Rockville, Maryland, USA.
5
Lymphocyte Biology Section, Laboratory of Systems Biology, NIAID, NIH, Bethesda, Maryland, USA.
6
Biological Imaging Section, Research Technologies Branch, NIAID, NIH, Bethesda, Maryland, USA.
7
Department of Biochemistry, Faculty of Science, Charles University in Prague, Prague, Czech Republic.
8
Department of Chemistry, University of California, Irvine, Irvine, California, USA.

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.

Comment in

PMID:
26501954
PMCID:
PMC5842712
DOI:
10.1038/nbt.3371
[Indexed for MEDLINE]
Free PMC Article

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