In vivo characterization of the physicochemical properties of polymer-linked TLR agonists that enhance vaccine immunogenicity
Jazyk angličtina Země Spojené státy americké Médium print-electronic
Typ dokumentu časopisecké články, Research Support, N.I.H., Extramural, práce podpořená grantem
Grantová podpora
Z99 AI999999
Intramural NIH HHS - United States
K22 AI108628
NIAID NIH HHS - United States
C552/A17720
Cancer Research UK - United Kingdom
T32 GM145449
NIGMS NIH HHS - United States
17720
Cancer Research UK - United Kingdom
T32 GM007171
NIGMS NIH HHS - United States
PubMed
26501954
PubMed Central
PMC5842712
DOI
10.1038/nbt.3371
PII: nbt.3371
Knihovny.cz E-zdroje
- MeSH
- adjuvancia imunologická chemie MeSH
- myši inbrední C57BL MeSH
- myši MeSH
- nosiče léků chemie MeSH
- T-lymfocyty imunologie MeSH
- toll-like receptory agonisté MeSH
- vakcíny imunologie MeSH
- zvířata MeSH
- Check Tag
- mužské pohlaví MeSH
- myši MeSH
- ženské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Research Support, N.I.H., Extramural MeSH
- Názvy látek
- adjuvancia imunologická MeSH
- nosiče léků MeSH
- toll-like receptory MeSH
- vakcíny MeSH
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
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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