Safety and immunogenicity of HCV E1E2 vaccine adjuvanted with MF59 administered to healthy adults

Abstract

Background Hepatitis C virus (HCV) causes chronic liver disease that often leads to cirrhosis and hepatocellular carcinoma. In animal studies, chimpanzees were protected against chronic infection following experimental challenge with either homologous or heterologous HCV genotype 1a strains which predominates in the USA and Canada. We describe a first in humans clinical trial of this prophylactic HCV vaccine. Methods HCV E1E2 adjuvanted with MF59C.1 (an oil-in-water emulsion) was given at 3 different dosages on day 0 and weeks 4, 24 and 48 in a phase 1, placebo-controlled, dose escalation trial to healthy HCV-negative adults. Results There was no significant difference in the proportion of subjects reporting adverse events across the groups. Following vaccination subjects developed antibodies detectable by ELISA, CD81 neutralization and VSV/HCV pseudotype neutralization. There was no significant difference between vaccine groups in the number of responders and geometric mean titers for each of the three assays. All subjects developed lymphocyte proliferation responses to E1E2 and an inverse response to increasing amounts of antigen was noted. Conclusions The vaccine was safe and generally well tolerated at each of the 3 dosage levels and induced anti-body and lymphoproliferative responses. A larger study to further evaluate safety and immunogenicity is warranted.

Selection of Adjuvants for Enhanced Vaccine Potency

“…It has been shown to be effective for a HCV vaccine [133]. It can initiate greater, longer-lasting, and broader immune responses than a nonadjuvanted split flu vaccine in healthy young children [134,135] and in adults [136].…”

Native Folding of a Recombinant gpE1/gpE2 Heterodimer Vaccine Antigen from a Precursor Protein Fused with Fc IgG

“…Previously, GNA was used as an enrichment step for the isolation of recombinant E1E2 and E2 proteins (35,37,43). This method was also used successfully to obtain high-purity E1E2 for vaccination of human volunteers in a phase I HCV vaccine trial (38). However, isolation of E1E2 using GNA poses a significant challenge due to its lack of specificity (GNA binds to all branched high-mannose glycoproteins) and low target protein affinity (ϳ3 mg of target glycoprotein/ml of GNA).…”

“…For HCV, 1a E1E2 was shown previously to reduce the carrier rate in immunized chimpanzees and generate sterilizing immunity in some individuals in response to homologous and heterologous 1a virus challenges (35,36,57). Furthermore, E1E2 is the only candidate vaccine to demonstrate broad nAb responses from vaccinated human volunteers (38,39,41,42). Soluble forms of E2 can be produced from mammalian and insect cells (20,21,59,60), and rational vaccine design has been proposed based on E2 cross-neutralizing epitopes (19).…”

“…Sterilizing immunity was observed in some of these vaccinated animals (35)(36)(37). A phase I dose-ranging clinical trial was conducted on healthy human volunteers and demonstrated the induction of anti-E1E2 antibodies (determined by an enzyme immunoassay) and strong T-helper cell responses (38). Follow-up studies demonstrated that antibodies present in sera from vaccinated individuals could impair infection in vitro by HCV genotype 1a as well as other diverse genotypes (39)(40)(41).…”

Unraveling hepatitis C virus structure

“…This region appears as a target of primary interest for preventive strategies, especially immunoprevention of liver graft infection during liver transplantation and vaccine design. This last point is supported by encouraging results obtained in humans using an E1E2-based vaccine that induces neutralizing B cell responses [10], yet even these results were likely limited by poor folding of the recombinant HCV GP used. Thus, the present study gives new crucial structural information for the use of recombinant E2 protein as part of a preventive vaccine.…”