Vaccination for Hepatitis C Virus

Closing in on an Evasive Target

John Halliday; Paul Klenerman; Eleanor Barnes


Expert Rev Vaccines. 2011;10(5):659-672. 

In This Article

DNA Vaccines

In 2001, the first DNA vaccine was licensed for use to protect horses from West Nile virus.[93] Initial work in the decade leading up to this significant accomplishment demonstrated that injection of a plasmid containing a gene could effectively result in protein expression in vivo and subsequently induce a host immune response.[94–96] Substantial research efforts have been aimed at developing an effective hepatitis C DNA vaccine (Table 3).[97]

Unfortunately, the initial success observed with DNA vaccination-induced immunity in mice did not translate well into similar results in humans – probably, in part, because the efficacy of DNA uptake and gene expression decreases as the size of the immunized host grows.[98,99] Subsequently, several methods were developed to improve DNA delivery and hence immunogenicity. These methods include:

  • Biolistic technology (biological ballistic or 'gene gun'): tungsten particles are loaded with genetic material and, using a device known as a particle gun, fired at living plant cells.[100] This resulted in delivery of DNA into a proportion of plant cells. In 2000, a clinical trial using a gene gun for DNA vaccination against hepatitis B was performed with successful induction of protective humoral immunity as well as hepatitis B surface antigen-specific T-cell responses;[101]

  • Electroporation (EP): electrical impulses create transient pores in living cells and subsequently allow delivery of DNA across the cell membrane. The local damage to cell membranes is also thought to enhance the local inflammatory response.[102–104] EP, at least in mice, is said to enhance the immunogenic response by DNA vaccination tenfold. This method has been successfully used in DNA vaccine trials in prostate cancer and is currently under evaluation in a Phase I/II HCV trial.[105]

The first DNA-based vaccine to reach clinical trial for HCV infection did not employ either of these adjuvant vaccine delivery techniques. This Phase I trial based in Cuba evaluated a vaccine (CICGB-230) combining plasmid expressing HCV structural antigens (core/E1/E2) with recombinant core protein (Co.120).[106] A total of 15 patients with HCV genotype-1 infection who had previously failed PEG-IFN/ribavirin therapy received monthly intramuscular injections for 6 months. The vaccine was well tolerated. The T-cell response to the vaccine components (as well as NS3) was measured using ELISpot and proliferation assays 1 month following the final vaccine. Although low levels of T-cell immunity were observed in 11 patients, others showed a reduction in responses. Six patients developed weak de novo neutralizing antibody responses against heterologous viral pseudoparticles. Only one patient had a drop in viral load of >1 log10. In addition, the authors reported stabilization or improvement in liver histology, however, the absence of a control arm makes this finding difficult to interpret.

The second HCV DNA-based vaccine (ChronVac-C, Tripep) to reach human trials employed electroporation to enhance the immunogenicity of intramuscular injection of plasmid expressing HCV antigens NS3/4a. Extensive codon modification was undertaken to allow effective DNA expression and enhance in vivo T-cell responses. A total of 12, treatment-naive, genotype-1 HCV-infected patients with a low viral load (<800,000 IU/ml) received four monthly doses of DNA (three groups: 167, 500 and 1500 µg) in this Phase I/IIa clinical trial. Preliminary results from this trial were reported in 2009.[105] A total of 67% (four out of six) of patients who received the higher doses had reductions in viral load exceeding 0.5 log10 lasting for 2 to more than 10 weeks, with corresponding activation of T-cell responses in three of these patients. No severe adverse reactions were observed.


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