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.

Vector Vaccines

The use of viral vectors for the delivery of HCV RNA is an appealing vaccine choice. Adenoviral vectors have shown to be potent inducers of HCV-specific T-cell responses in the chimpanzee model and to reduce peak HCV viremia during primary infection.^[62] This approach may induce a broader range of viral epitopes than a peptide-based approach since the immunogen contained within the vaccine is not HLA restricted.

Modified vaccinia Ankara (MVA) is a highly attenuated poxvirus strain that has been used safely in several vaccine designs for conditions such as HIV, colorectal cancer, TB and melanoma. A therapeutic vaccine (TG4040) using MVA that expresses NS3/4/5B proteins has been evaluated for safety and immunogenicity in an open-label, multicenter, dose-escalation study (Table 4). Preliminary results were presented at the European Association for the Study of Liver Disease conference in 2009.^[107] A total of 15 chronically infected HCV patients received three weekly injections, nine of whom received a fourth injection at 6 months. In six out of 15 patients, a decline in HCV viral load (0.5–1.4 log₁₀) was observed in association with a significant CD8⁺ T-cell response. A Phase II trial using the vaccine in combination with standard treatment is planned.^[203]

Adenovirus vectors are also being employed in a Phase I vaccine trial to deliver NS HCV proteins (NS3–5B) to 36 healthy volunteers.^[204] The vaccine vectors are genetically modified so that they are unable to replicate and the polymerase activity of the NS proteins is inactivated to further enhance vaccine safety. To overcome the problem of pre-existing anti-adenoviral antibodies, which may limit vector efficacy, two adenoviral vectors to which humans are rarely exposed are used: Ad6 and a simian vector AdCh3. Early data from this trial were presented at the American Association for the Study of Liver Disease in 2009 where this approach was reported to be highly immunogenic in healthy volunteers following a single priming injection (Ad6).^[73] Further studies are planned in HCV-infected patients.

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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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