Inactivated whole hepatitis C virus vaccine employing a licensed adjuvant elicits cross-genotype neutralizing antibodies in mice

Abstract

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Inactivated genotype 1a, 2a and 3a HCV vaccine candidates induced broadly neutralising antibodies in mice

“…Fifty per cent neutralisation titres and ELISA endpoint titres of vaccine-induced antibodies were comparable with those reported for licenced antiviral vaccines and with those in chimpanzees protected from HCV challenge following vaccination with the E1/E2 heterodimer vaccine 6 10. However, compared with IgG from chronically infected patients, antibodies elicited by the E1/E2 heterodimer vaccine8–10 and different vaccine candidates based on soluble E2 protein,46 49–51 nAb induced in this and the previous study35 showed increased capacity to neutralise different HCV variants. Finally, 50% neutralisation titres were comparable with those reported for a genotype 2a inactivated vaccine candidate in mice and non-human primates when experimental adjuvants not suitable for human use were applied 21 29.…”

“…For HCV, deletion of HVR1 led to a maximally open E1/E2 state associated with high neutralisation sensitivity 19 40. For the full length genotype 1–3 HI-viruses developed in this study and the previously developed JFH1-based high-yield genotype 5a HCV,31 the AR3A epitopes were as accessible as in HVR1-deleted viruses, while the AR4A epitopes were approximately 10-fold to 100-fold less exposed 35 40. However, HVR1-deleted viruses typically show relatively low infectivity titres, hampering vaccine production 48.…”

“…In the study of non-human primates, application of the licenced adjuvant aluminium hydroxide did not result in induction of efficient nAb 29. AddaVax/MF-59 appears to be more immunogenic than aluminium hydroxide 35 52. Furthermore, for other viruses, increased neutralising epitope exposure was suggested to result in increased immunogenicity 53 54.…”

“…However, HVR1-deleted viruses typically show relatively low infectivity titres, hampering vaccine production 48. Compared with the original viruses, HI-viruses showed ~300 to 1250-fold higher exposure of AR3A epitopes and ~12 to 2400-fold higher exposure of AR4A epitopes; the high-yield genotype 5a HCV showed only ~10 fold higher exposure of AR3A and AR4A epitopes than the original already highly neutralisation sensitive genotype 5a HCV 35…”

“…HCV was clarified using 5 µm and 0.65 µm filters and concentrated by tangential flow filtration (TFF) with molecular weight cut-off (MWCO) 500 kDa,36 followed by two ultracentrifugation steps using Optiprep Density Gradient Medium (Sigma) for formation of three density cushions and a continuous gradient, respectively, separated by an intermediate TFF step (MWCO 500 kDa). Following size exclusion chromatography using Sephadex G-100 (Sigma Aldrich), HCV was UV irradiated with a UVG-54 Handheld UV lamp (240 nm UV, 6 watt) (Analytik Jena) 35…”