Hepatitis C VLPs Delivered to Dendritic Cells by a TLR2 Targeting Lipopeptide Results in Enhanced Antibody and Cell-Mediated Responses

Abstract

Although many studies provide strong evidence supporting the development of HCV virus-like particle (VLP)-based vaccines, the fact that heterologous viral vectors and/or multiple dosing regimes are required to induce protective immunity indicates that it is necessary to improve their immunogenicity. In this study, we have evaluated the use of an anionic self-adjuvanting lipopeptide containing the TLR2 agonist Pam2Cys (E8Pam2Cys) to enhance the immunogenicity of VLPs containing the HCV structural proteins (core, E1 and E2) of genotype 1a. While co-formulation of this lipopeptide with VLPs only resulted in marginal improvements in dendritic cell (DC) uptake, its ability to concomitantly induce DC maturation at very small doses is a feature not observed using VLPs alone or in the presence of an aluminium hydroxide-based adjuvant (Alum). Dramatically improved VLP and E2-specific antibody responses were observed in VLP+E8Pam2Cys vaccinated mice where up to 3 doses of non-adjuvanted or traditionally alum-adjuvanted VLPs was required to match the antibody titres obtained with a single dose of VLPs formulated with this lipopeptide. This result also correlated with significantly higher numbers of specific antibody secreting cells that was detected in the spleens of VLP+E8Pam2Cys vaccinated mice and greater ability of sera from these mice to neutralise the binding and uptake of VLPs by Huh7 cells. Moreover, vaccination of HLA-A2 transgenic mice with this formulation also induced better VLP-specific IFN-γ-mediated responses compared to non-adjuvanted VLPs but comparable levels to that achieved when coadministered with complete freund’s adjuvant. These results suggest overall that the immunogenicity of HCV VLPs can be significantly improved by the addition of this novel adjuvant by targeting their delivery to DCs and could therefore constitute a viable vaccine strategy for the treatment of HCV.

Characterization of a hepatitis C virus-like particle vaccine produced in a human hepatocyte-derived cell line

“…HCV virus-like particles (VLPs) could serve as a viable vaccine candidate for HCV as they are able to produce both NAb and cellular immune responses (Beaumont et al, 2013;Chua et al, 2012;Patient et al, 2009). Furthermore, as HCV-specific NAbs recognize tertiary or quaternary structures (Giang et al, 2012), the repetitive and ordered particulate structure of HCV VLPs makes VLPs an attractive vaccine candidate (Beaumont et al, 2013;Chua et al, 2012;Elmowalid et al, 2007;Garrone et al, 2011).…”

“…Furthermore, as HCV-specific NAbs recognize tertiary or quaternary structures (Giang et al, 2012), the repetitive and ordered particulate structure of HCV VLPs makes VLPs an attractive vaccine candidate (Beaumont et al, 2013;Chua et al, 2012;Elmowalid et al, 2007;Garrone et al, 2011).…”

“…We have previously shown that mammalian-cell-derived HCV VLPs adjuvanted with Toll-like receptor 2 (TLR2) agonists are strongly immunogenic (Chua et al, 2012). In this study we have focussed on describing the biochemical and morphological characterization of our genotype 1a HCV VLP vaccine.…”

Progress in Vaccine Development for HCV Infection

“…HCV-specific neutralizing antibodies (Nabs) recognize quaternary structures [43,44]. The particulate structure of HCV VLPs makes them an attractive vaccine candidate [45][46][47].…”

Prophylactic vaccinations in chronic kidney disease: Current status

“…17 TLR agonists were already used as vaccine adjuvants and are being tried in elaboration of novel vaccines. 18 Significantly altered B cell-associated immunity is a wellknown phenomenon related to GFR category 5 (end-stage renal disease, ESRD). 19 Pahl et al clearly showed that B-cell lymphopenia is associated with the downregulation of B-cell activating factor (BAFF) receptor in transitional B cells.…”