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.
Highlights
Hepatitis C virus (HCV) infection affects an estimated 200 million individuals worldwide and contributes to significant morbidity and mortality rates associated with liver cirrhosis and hepatocellular carcinoma
Because of the essential role that dendritic cell (DC) play in the induction of both humoral and cell-mediated responses, we first examined the ability of a spleen-derived DC line (D1 cells) to take up fluorescein isothiocyanate-labelled HCV virus-like particle (VLP) (FITC-VLPs)
Flow cytometric analysis revealed that DCs incubated with FITC-VLPs exhibited higher whole cell fluorescence intensities compared to untreated DCs indicating the presence of cell-associated VLPs (Figure 1B)
Summary
Hepatitis C virus (HCV) infection affects an estimated 200 million individuals worldwide and contributes to significant morbidity and mortality rates associated with liver cirrhosis and hepatocellular carcinoma. 80% of infected individuals do not clear the virus following acute infection and will develop chronic infection that can lead to end-stage liver disease and complications. Treatment options using a combination of pegylated interferon-a and ribavirin are available, sustained clearance of the virus is only achieved in approximately 40% of individuals infected with HCV genotype 1 and 60–70% of those who are infected with genotypes 2 or 3 [1]. Treatment can be prolonged, expensive and associated with substantial side effects. The development of an effective vaccine that can significantly reduce the number of new infections and improve sustained virological response rates could be a useful adjunct to current therapeutic approaches and reduce the impact of infection on global health care systems
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