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.

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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Table 1. Recombinant protein hepatitis C vaccine studies.
Structure (Investigator)	Phase (year)	Subjects	Outcome	Ref.
HCV E1 + alum adjuvant (Innogenetics/GenImmune)	I (2003)	20 healthy volunteers + 34 HCV-infected, treatment-naive patients	Well tolerated. No HCV viral load change. 50 out of 54 patient T-cell response. Humoral response correlated with improvement in ALT and liver histology	[77,78]
	II (2008)	122 HCV-infected patients randomized (3:1)	Well tolerated. Induced humoral and cellular immune responses. No change in histological progression of liver disease over 3 years	[79]
HCV E1/E2 glycoproteins/MF59C adjuvant (Novartis)	I (2010)	60 healthy volunteers	Well tolerated. Induced antibody and E1/E2-specific T-cell responses in all patients independent of vaccine dose	[76]
GI5005: recombinant yeast transfected with HCV NS3–core fusion protein (Globeimmune)	II (2009)	66 patients with chronic HCV-G1 (treatment-naive and nonresponders)	17% SVR with vaccine + standard care, compared with standard therapy response of 5% in prior nonresponders	[80]
HCV core protein/ISCOMATRIX® (CSL Ltd)	I/IIa (2009)	30 healthy volunteers	Well tolerated, mild local redness; all developed antibody response	[82]

Recombinant protein hepatitis C vaccine advantages: well tolerated with low toxicity; induces cross-neutralizing antibodies; proof-of-concept (HBV vaccine).
Disadvantages: generally only weak T-cell responses elicited.
ALT: Alanine transaminase; HCV: Hepatitis C virus; SVR: Sustained virological response.

Table 2. Peptide hepatitis C vaccine studies.
Structure (Investigator)	Phase (year)	Subjects	Outcome	Ref.
IC41: five peptides from core, NS3 and NS4 + poly-l-arginine adjuvant (Intercell AG)	II (2008)	60 chronic HLA A2 HCV-infected nonresponders	Well tolerated. 67% T-cell response. Transient serum HCV RNA decline (>1 log) in three patients	[84]
Peptide derived from core protein (C35–44) (Karume University)	I (2009)	26 patients with chronic HCV (23 nonresponders, three untreated)	Well tolerated. 15 out of 25 responded, two out of 25 had a 1 log decline in HCV RNA	[90]
Personalized peptide approach CD8+ A24 peptides + Freund's adjuvant (Karume University)	I (2007)	12 chronic HCV-1b-infected nonresponders	Well tolerated. Majority developed peptide-specific T-cell responses. Five patients reduced ALT and three patients had a HCV RNA decline	[91]
Autologous dendritic cell delivered HLA A2 epitopes (Burnet Institute + others)	I (2010)	Six chronic HCV-infected nonresponders	Well tolerated. Transient T-cell responses	[92]
NS3/Virosome (Pevion Biotech)	N/A	30 healthy volunteers	Results pending

Peptide hepatitis C vaccine advantages: well tolerated with low toxicity; induces both cellular and humoral responses.
Disadvantages: limited immunogenicity (few epitopes only); need to tailor to patient HLA type; concern regarding appropriate peptide choice (e.g., induce Tregs rather than CD8⁺ cells).
ALT: Alanine transaminase; HCV: Hepatitis C virus; N/A: Not available.

Table 3. DNA hepatitis C vaccine studies†.
Structure/vector (Investigator)	Phase (year)	Subjects	Outcome	Ref.
CICGB-230: plasmid core/E1/E2 + recombinant core protein (University of Montreal + others)	I (2009)	15 genotype-1- infected nonresponders	Well tolerated, no viral clearance, 11 out of 15 – weak specific T-cell responses (ELISpot and proliferation). Six out of 15 – weak humoral response	[106]
ChonVac-C: plasmid NS3/4a + electroporation (Tripep)	I/IIa (2009)	12 HCV-1-infected, treatment-naive patients	Well tolerated. A total of four out of six who received higher doses: viral load reduction >0.5 log with corresponding T-cell response in three patients	[105]

†Ideal genes should represent part of the genome with limited genetic variability and maximal immunogenicity.
DNA hepatitis C vaccine advantages: presents a broad range of epitopes.
Disadvantage: electroporation is painful.
ELISpot: Enzyme-linked immunosorbent spot; HCV: Hepatitis C virus.

Table 4. Viral-vectored hepatitis C vaccine studies.
Structure/vector (Investigator)	Phase (year)	Subjects	Outcome	Ref.
TG4040: MVA vector expressing NS3/4/5B proteins (Transgene)	I (2009)	15 chronically infected HCV patients	A total of six out of 15 declined HCV viral load (0.5– 1.4 log) associated with T-cell response (IFN-g ELISpot)	[107]
Adenovirus vector (Ad6 and AdCh3) expressing NS3–5B proteins (Okairos and Oxford University).	I (2009)	36 healthy volunteers	Highly immunogenic and well tolerated	[73]

Viral-vectored hepatitis C vaccine advantages: efficient induction of cellular immune responses; presentation of a broader range of viral epitopes.
Disadvantages: pre-existing immunity to viral vector (adenovirus; may be overcome by the use of rare serotypes); limited experience in humans.
Ad: Adenovirus; ELISpot: Enzyme-linked immunosorbent spot; HCV: Hepatitis C virus; MVA: Modified vaccinia Ankara.

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