Potent anti-viral vaccine adjuvant based on pH-degradable nanogels with covalently linked small molecule imidazoquinoline TLR7/8 agonist

Lutz Nuhn; Lien Van Hoecke; Kim Deswarte; Bert Schepens; Yupeng Li; Bart N Lambrecht; Stefaan De Koker; Sunil A David; Xavier Saelens; Bruno G De Geest

doi:10.1016/j.biomaterials.2018.03.026

Potent anti-viral vaccine adjuvant based on pH-degradable nanogels with covalently linked small molecule imidazoquinoline TLR7/8 agonist

Biomaterials. 2018 Sep:178:643-651. doi: 10.1016/j.biomaterials.2018.03.026. Epub 2018 Mar 16.

Authors

Affiliations

¹ Department of Pharmaceutics, Ghent University, Ottergemsesteenweg 460, 9000 Ghent, Belgium; Max Planck Institute for Polymer Research, Ackermannweg 10, 55128 Mainz, Germany.
² VIB-UGent Center for Medical Biotechnology, VIB, Technologiepark 927, 9052 Zwijnaarde, Belgium; Department of Biomedical Molecular Biology, Ghent University, Technologiepark 927, 9052 Ghent, Belgium.
³ VIB-UGent Center for Inflammation Research, VIB, Technologiepark 927, 9052 Zwijnaarde, Belgium; Department of Respiratory Medicine, University Hospital Ghent, 9000 Ghent, Belgium.
⁴ Department of Medicinal Chemistry, University of Minnesota, Minneapolis, MN 55455, USA.
⁵ Department of Pharmaceutics, Ghent University, Ottergemsesteenweg 460, 9000 Ghent, Belgium. Electronic address: [email protected].

PMID: 29573820
DOI: 10.1016/j.biomaterials.2018.03.026

Abstract

Improving the immunogenicity of subunit vaccines, in particular skewing of the immune response towards Th1 type immunity, is crucial for the development of effective vaccines against intracellular infections and for the development of anti-cancer vaccines. Small molecule TLR7/8 agonist hold high potential for this purpose, but suffer from an undesirable pharmacokinetic profile, resulting in systemic inflammatory responses. An effective solution to this problem is covalent ligation to a larger carrier. Here, a degradable nanogel carrier containing a covalently linked imidazoquinoline (IMDQ) TLR7/8 agonist is explored as adjuvant for vaccination against the respiratory syncytial virus (RSV). In vitro and in vivo experiments in mice provide a solid rational base for preferring nanogels over soluble polymers as IMDQ carrier in terms of cellular uptake and lymph node accumulation.

Keywords: Lymph nodes; Nanogels; RSV; TLR agonist; Vaccine.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Adjuvants, Immunologic / pharmacology*
Animals
Antiviral Agents / pharmacology*
Female
Hydrogen-Ion Concentration
Imidazoles / chemistry
Imidazoles / pharmacology*
Mice, Inbred BALB C
Nanogels
Polyethylene Glycols / chemistry*
Polyethyleneimine / chemistry*
Quinolines / chemistry
Quinolines / pharmacology*
Small Molecule Libraries / pharmacology
Toll-Like Receptor 7 / agonists*
Toll-Like Receptor 7 / chemistry
Toll-Like Receptor 8 / agonists*
Toll-Like Receptor 8 / chemistry
Viral Vaccines / immunology*

Substances

Adjuvants, Immunologic
Antiviral Agents
Imidazoles
Nanogels
Quinolines
Small Molecule Libraries
Toll-Like Receptor 7
Toll-Like Receptor 8
Viral Vaccines
polyethylene glycol polyethyleneimine nanogel
Polyethylene Glycols
Polyethyleneimine

Grants and funding

HHSN272201400056C/AI/NIAID NIH HHS/United States