Therapeutic vaccination of chronic hepatitis C nonresponder patients with the peptide vaccine IC41.

BACKGROUND & AIMS: IC41 is a synthetic peptide vaccine containing 7 relevant hepatitis C virus (HCV) T-cell epitopes and the T helper cell (Th)1/Tc1 adjuvant poly-L-arginine. IC41 has been shown to be safe and to induce HCV-specific interferon (IFN)-gamma-secreting CD4+ and CD8+ T cells in healthy volunteers. We aimed to investigate whether IC41 is able to induce HCV-specific T-cell responses also in chronic hepatitis C patients. METHODS: Sixty HLA-A2-positive chronic HCV patients not responding to or relapsing from standard therapy were randomized in a double-blind phase II study into 5 groups to receive 6 vaccinations of IC41 (3 different dose groups), HCV peptides alone, or poly-L-arginine alone. RESULTS: IC41 was well tolerated, and no drug-related serious adverse events or induction of hepatitis were observed. T-cell proliferation was recorded in up to 67% of patients in the 3 IC41 vaccine groups but only in 17% of patients treated with peptides alone. IFN-gamma enzyme-linked immunospot assay responses were observed exclusively in the IC41 groups with response rates up to 42%. There were 3 RNA responders with transient >1-log declines of HCV serum RNA associated with the strongest IFN-gamma enzyme-linked immunospot assay values within all 60 patients. CONCLUSIONS: This study showed that the HCV peptide vaccine IC41 can induce HCV-specific Th1/Tc1 responses in a subset of difficult to treat HCV nonresponder patients despite persisting viremia. However, changes in HCV RNA occurred only in single patients. Because strongest T-cell responses were associated with HCV RNA decline, further studies with optimized vaccine regimens and combination therapies have been initiated.

Functional and phenotypic characterization of peptide-vaccine-induced HCV-specific CD8+ T cells in healthy individuals and chronic hepatitis C patients.

Only very limited information on phenotype and function of vaccine-induced CD8+ T cells is available for humans. We investigated hepatitis C virus-specific CD8+ T cells after vaccination with the HCV peptide-vaccine IC41 which includes 5 MHC-class I and 3 MHC class-II-restricted epitopes. In healthy subjects, IC41 induced both HCV-specific central memory as well as effector CD8+ T cells which rapidly expanded upon antigen exposure in vitro. IFNgamma production was dependent on formulation of the synthetic peptides with the adjuvant poly-l-arginine. In chronic HCV patients, the frequency of HCV-specific CD8+ T cells increased after vaccination with a decline of CD45RA-positive effector memory cells in some but not all patients. Thus, this study suggests that HCV-specific memory cells can be induced by peptide vaccination and that a reversion of functional impaired phenotypes by therapeutic vaccination is possible in chronic HCV infection.

Immunogenicity and safety of a novel therapeutic hepatitis C virus (HCV) peptide vaccine: a randomized, placebo controlled trial for dose optimization in 128 healthy subjects.

As interferon/ribavirin-based standard therapy is curative in only about half of HCV patients, there remains an important need for alternatives including vaccines. The novel peptide vaccine IC41 consists of five synthetic peptides harboring HCV T cell epitopes and poly-L-arginine as synthetic adjuvant. In this randomized, placebo-controlled trial, 128 HLA-A2 positive healthy volunteers received four s.c. vaccinations of seven different doses IC41, HCV peptides alone, poly-l-arginine alone or saline solution, every 4 weeks. IC41 was safe and well tolerated. Mild to moderate local reactions were transient. Immunogenicity was assessed using T cell epitope specific [3H]-thymidine proliferation, IFN-gamma ELIspot and HLA-tetramer assays. IC41 induced responses in all dose groups. Higher responder rates were recorded in higher dose groups and increasing number of vaccinations were associated with higher responder rates and more robust responses. Poly-L-arginine was required for the aimed-for Th1/Tc1-type immunity (IFN-gamma secreting T cells).