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 Need for a Therapeutic HCV Vaccine

Current gold-standard therapy for HCV infection is weekly subcutaneous injections of pegylated interferon (PEG-IFN) combined with daily oral ribavirin for a period of 24 weeks for genotypes 2 and 3, and 48 weeks for genotypes 1 and 4. Therapy is fraught with significant side effects and leads to a sustained virological response (SVR; patients are negative for the virus by reverse transcription PCR 6 months after finishing therapy) in approximately 40–50% of patients with genotype 1 infection, 65–70% with genotype 3 and 80% of those with genotype 2. PEG-IFN and ribavirin treatment is also expensive and, at an average cost of approximately GB£7000 in the UK for a treatment course, is unaffordable in developing countries.^[16]

Two viral protease inhibitors (telaprevir and boceprevir) are currently in Phase III clinical trials for HCV and more are in development. These drugs will need concomitant PEG-IFN/ribavirin therapy to avoid the rapid emergence of viral mutants and are currently only effective against genotype 1 infection. It is expected they will increase SVR rates following treatment to 70%.^[17,18] Because these drugs will be used together with PEG-IFN/ribavirin, the cost of treatment will rise further and additional side effects, in particular skin rashes, can be anticipated. The cost of a 3-month course of protease inhibitor in the UK is currently predicted to be GB£18,000–22,000 [Vertex Pharmaceuticals, Pers. Comm.]. Many other direct antiviral therapies are in development but these are unlikely to reach clinical application in the next few years.

Interestingly, the SVR rate of individuals that are treated in the early phase of infection with IFN alone is very high (70–90%).^[19] The reasons for this are not known but may relate to the fact that the infecting virus has not yet evolved to subvert the effects of IFN – or alternatively, that IFN therapy harnesses the host's robust natural immunity that is present in acute infection in a way that it is unable to do so once chronic infection is established. Similarly, it is plausible that a therapeutic vaccination strategy may prove more efficacious in early infection. In clinical practice, however, acute infection is frequently asymptomatic and patients usually do not present to clinicians until chronic infection is established.

Clearly, a therapeutic vaccine that increases SVR rates in chronic infection, or reduces the duration of therapy would represent a major step forward.

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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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