Vaccination for Hepatitis C Virus

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.

†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.

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.

Authors and Disclosures

John Halliday¹, Paul Klenerman², and Eleanor Barnes<sup>†2

1</sup>Translational Gastroenterology Unit, John Radcliffe Hospital, Oxford, UK
²Peter Medawar Building for Pathogen Research and Oxford NIHR Biomedical Research Centre, Nuffield Department of Medicine, University of Oxford, UK

^†Author for correspondence
Tel.: +44 187 527 1199 Fax: +44 186 528 1890 ellie.barnes@ndm.ox.ac.uk

Sidebar

Key Issues

• Hepatitis C virus (HCV) infects more than 170 million people globally and is now the leading cause of liver transplantation worldwide.

• A total of 20% of acute HCV infections in humans will clear spontaneously – clearance is associated with some degree of (but not complete) protective immunity.

• Current gold-standard treatment is prolonged, fraught with side effects, often ineffective and prohibitively expensive in developing countries.

• The host T-cell response is most important in determining the outcome of acute HCV infection but humoral and innate immune responses are also important.

• During chronic HCV infection, the host HCV-specific T-cell response is impaired – whether this is a consequence or a cause of chronic infection is not known.

• HCV has a remarkable ability to evade the natural host immune response through a number of mechanisms including genetic variation.

• It is unlikely that sterilizing immunity can be obtained through vaccination, but a vaccine that attenuates the course of primary infection may afford protection from chronic carriage.

• Many promising vaccine approaches have reached clinical trials including peptide, protein, DNA and vector-based vaccines.

• A successful T-cell vaccine strategy will need to induce a broad and strong T-cell response. Adenoviral vectors are highly immunogenic in healthy volunteers; it is not yet known if these vaccines can adequately recover T-cell responses in HCV-infected patients.

• Well-characterized cohorts of at-risk and acutely infected HCV patients are required to move Phase I vaccine studies forward into studies of efficacy.