Antiviral Res. 2020 Feb 17:104746. doi: 10.1016/j.antiviral.2020.104746. [Epub ahead of print]
Design of TLR2-ligand-synthetic long peptide conjugates for therapeutic vaccination of chronic HBV patients.
Dou Y1, Jansen DTSL1, van den Bosch A1, de Man RA1, van Montfoort N1, Araman C2, van Kasteren SI2, Zom GG3, Krebber WJ3, Melief CJM3, Woltman AM1, Buschow SI4.
Author information
1
Department of Gastroenterology and Hepatology, Erasmus MC, University Medical Center Rotterdam, the Netherlands.
2
Leiden Institute of Chemistry and the Institute for Chemical Immunology, Leiden University, Einsteinweg 55, 2333, CC Leiden, the Netherlands.
3
ISA Pharmaceuticals BV, Leiden, the Netherlands.
4
Department of Gastroenterology and Hepatology, Erasmus MC, University Medical Center Rotterdam, the Netherlands. Electronic address: [email protected].
Abstract
Synthetic long peptide (SLP) vaccination is a promising new treatment strategy for patients with a chronic hepatitis B virus (HBV) infection. We have previously shown that a prototype HBV-core protein derived SLP was capable of boosting CD4+ and CD8+ T cell responses in the presence of a TLR2-ligand in chronic HBV patients ex vivo. For optimal efficacy of a therapeutic vaccine in vivo, adjuvants can be conjugated to the SLP to ensure delivery of both the antigen and the co-stimulatory signal to the same antigen-presenting cell (APC). Dendritic cells (DCs) express the receptor for the adjuvant and are optimally equipped to efficiently process and present the SLP-contained epitopes to T cells. Here, we investigated TLR2-ligand conjugation of the prototype HBV-core SLP. Results indicated that TLR2-ligand conjugation reduced cross-presentation efficiency of the SLP-contained epitope by both monocyte-derived and naturally occurring DC subsets. Importantly, cross-presentation was improved after optimization of the conjugate by either shortening the SLP or by placing a valine-citrulline linker between the TLR2-ligand and the long SLP, to facilitate endosomal dissociation of SLP and TLR2-ligand after uptake. HBV-core SLP conjugates also triggered functional patient T cell responses ex vivo. These results provide an import step forward in the design of a therapeutic SLP-based vaccine to cure chronic HBV.