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.

Peptide Vaccines

Like recombinant protein vaccines, peptide-based vaccines are well tolerated (Table 2). They induce HCV-specific T-cell immunity through the direct presentation of vaccine peptide to the T-cell receptor via HLA molecules. However, the major limitation of this approach is that peptide vaccines are HLA-specific and, as such, coverage will be restricted to a subset of the population. Additionally, HCV peptide vaccines to date have included only a handful of peptides – and the breadth of the induced T-cell response may be insufficient to control infection. In addition, some peptides may potentially induce tolerance of effector cells or Treg cells rather than inducing immunity.^[83]

IC41 is a peptide vaccine currently in clinical development. It consists of five synthetic peptides from core, NS3 and NS4 proteins that are conserved across HCV genotypes 1 and 2, combined with the adjuvant poly-L-arginine. The peptides include three CD4⁺ T-cell and five HLA A2-restricted CD8⁺ T-cell HCV epitopes. In a Phase II, double-blind study, this vaccine was administered subcutaneously to 36 HLA A2 patients with genotype 1 chronic HCV infection who had previously been nonresponsive to PEG-IFN/ribavirin and compared with 24 controls.^[84] The vaccine was well tolerated with no serious adverse events. Weak HCV-specific T-cell proliferative and IFN-γ enzyme-linked immunosorbent spot (ELISpot) responses were observed in 67 and 42% of patients, respectively. Three responders with the strongest IFN-γ-secreting T-cell response had a transient decline in serum RNA (>1 log). A subsequent Phase II study combined IC41 with PEG-IFN/ribavirin therapy in 35 patients with HCV genotype 1 infection. T-cell responses were observed in 73% of vaccinated patients and associated with higher rates of viral clearance.^[85] The lack of an unvaccinated control arm makes it difficult to draw any significant conclusion regarding vaccine efficacy.

More recently, biweekly intradermal IC41 administration was found to induce stronger T-cell responses compared with the original monthly subcutaneous injection approach.^[86] This optimized vaccine schedule has been tested in 50 patients with chronic hepatitis C. A significant decline in viral load was observed after 4 months according to results currently presented in abstract form only.^[87] Intercell AG (Austria, Vienna), the company developing IC41, recently announced plans for a Phase II trial to begin in 2011 that will combine IC41 with nitazoxanide (a new broad-spectrum antiviral drug^[88,89]) in 60 treatment-naive genotype-1-infected HCV patients.

In 2009, a peptide derived from HCV core region (C35–44) was evaluated in a Phase I, dose-escalation, Japanese study of 26 patients (23 nonresponders to PEG-IFN/ribavirin and three who had declined standard therapy).^[90] A series of six biweekly subcutaneous injections was sufficient to induce peripheral peptide-specific CD8⁺ activity in 15 out of 25 patients (measured with ELISpot) and 12 injections augmented peptide-specific IgG production. A greater than 30% improvement in alanine transaminase was observed in seven out of 24 patients and two patients had a >1 log reduction in viral load. Further evaluation with a Phase II study is under consideration.

Another Japanese study adopted a 'personalized' peptide vaccine approach. In this study, 12 patients with HCV-1b, who had previously failed PEG-IFN/ribavirin therapy, were administered four CD8⁺ A24 peptides in combination with Freund's adjuvant. Only those peptides that induced an immune response in each individual following the first vaccine dose were then administered fortnightly for another 14 vaccinations.^[91] At the first assessment (following seven vaccine doses), the majority of patients had developed peptide-specific T-cell responses. A dose-dependent decrease in serum alanine transaminase and HCV RNA levels was observed in five and three patients, respectively.

A novel method of peptide delivery using autologous monocyte-derived dendritic cells was recently explored in a small Australian study.^[92] Dendritic cells were first harvested and then loaded and activated ex vivo with HLA A2 1-restricted T-cell epitopes. Six patients chronically infected with HCV who had previously failed PEG-IFN/ribavirin therapy received the vaccine. All patients developed weak de novo HCV-specific CD8⁺ T-cell responses (measured by IFN-γ ELISpot assays). The authors hypothesize that T-cell responses induced to viral epitopes not included in the vaccine may have been caused by epitope spreading. There was no change in viral load or anti-HCV core antibody levels and T-cell responses were not sustained.

Finally, a Phase I, placebo-controlled trial assessing a virosome-based vaccine containing NS3 peptides has recently been completed but no data have been released.^[202]

In summary, peptide-based vaccines are well tolerated and able to induce weak peptide-specific T-cell and humoral responses. Efficacy needs to be optimized, as trials show a significant reduction in viral load in only a few 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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