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.

The Ideal Vaccine

The Requirements…

Based on the viral–host interactions of HCV infection, as delineated in the previous sections, there are three characteristic properties that are likely to be shared by successful preventive and therapeutic vaccine approaches alike:

These vaccines will need to deal with high levels of viral genetic diversity both between and within hosts – as such, vaccines that target relatively conserved viral regions will be required;
The 'magnitude' of antiviral immunity associated with viral control is not precisely defined. Nevertheless, it is likely that a robust, broad and functional T cell, and possibly also a humoral, immune response will be required;
Clearly, to be safe, a successful vaccine will need to eradicate HCV from the liver without inducing liver immunopathology. Human studies to date suggest that this is a realistic goal.

…and the Challenges

In addition to overcoming the diverse mechanisms by which HCV evades immune clearance, there are practical obstacles that have hindered the development of both a preventive and therapeutic HCV vaccine. HCV is highly fastidious and there is no readily accessible animal model of infection. In 2003, study of viral entry and antibody-mediated neutralization was enabled for the first time through the development of retroviral particles pseudotyped with HCV envelope glycoproteins.^[59] It was not until 2005 that a successful tissue model of HCV infection was developed.^[60] This model uses the human hepatoma cell line Huh-7 and a unique viral variant capable of ongoing viral replication. This discovery allowed researchers to characterize the viral life cycle and viral–host interactions during infection for the first time. Transgenic mice expressing human MHC class I molecules have been used for specific HCV epitope analysis. Severe combined immunodeficieny (SCID) mouse models with chimeric human livers have been used to evaluate in vivo effects of antibodies to envelope glycoproteins.^[61]

To date, the only immunocompetent animal model for the pathogenesis or immune control of viral infection is the chimpanzee. This model has proved very useful in the preclinical phases of vaccine development since the immune mechanisms associated with viral control are broadly similar. For example, a study by Folgori was clearly able to demonstrate a reduction in HCV viremia, associated with the induction of robust immunity, using a small number of animals.^[62] This study subsequently facilitated the use of adenoviral vector technology in human trials. However, there are practical, financial and, for some, ethical limitations in using these animals for research.^[63] As a result, the small number of chimpanzees that can be used in HCV studies may limit the power of any conclusions that can be drawn.

Designing clinical studies in humans to evaluate a prophylactic vaccine is also challenging since the incidence of HCV infection in developed countries is relatively low other than in intravenous drug-using populations – targeting this patient group raises its own set of ethical and practical difficulties.^[64] Large studies in developing countries where the incidence may be higher raises logistical difficulties. Assessing the efficacy of a prophylactic HCV vaccine will require large numbers of patients and careful follow-up, since acute infection is often asymptomatic. Furthermore, it is possible that a prophylactic vaccine may be unable to achieve sterilizing immunity. However, a vaccine that led to an attenuated course of acute infection associated with viral clearance may be sufficient to ultimately prevent chronic infection, as has been suggested by studies in the chimpanzee model.^[62] In addition, this has study design implications; careful consideration must be given to the timing of IFN therapy during primary infection, in the context of a clinical study that is assessing vaccine efficacy. In theory, the vaccine may facilitate viral clearance weeks after current guidelines suggest IFN treatment should be given.

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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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