Gastroenterology

Gastroenterology

Volume 141, Issue 3, September 2011, Pages 890-899.e4
Gastroenterology

Original Research
Clinical—Liver
A Poxvirus Vaccine Is Safe, Induces T-Cell Responses, and Decreases Viral Load in Patients With Chronic Hepatitis C

https://doi.org/10.1053/j.gastro.2011.06.009Get rights and content

Background & Aims

Therapy for chronic hepatitis C (CHC) has limited efficacy, adverse effects, and high costs. Cohort and vaccine-based preclinical studies have indicated the importance of T-cell–based immunity in controlling viral infection. TG4040 is a recombinant poxvirus vaccine that expresses the hepatitis C virus (HCV) proteins NS3, NS4, and NS5B. We performed a phase I clinical trial to assess the safety, immunogenicity, and early antiviral efficacy of TG4040 in patients with CHC.

Methods

In an open-label, dose-escalating study, patients with mild CHC (genotype 1) were assigned to 3 groups of 3 patients each; they received subcutaneous injections of 106, 107, or 108 plaque-forming units of TG4040 on study days 1, 8, and 15. Six additional patients were given the highest dose of vaccine (108 plaque-forming units). Patients were followed for 6 months after the last injection. T-cell–based and antibody responses and levels of HCV RNA were measured.

Results

All 3 doses of TG4040 were well tolerated, without serious adverse events. Vaccine-induced HCV-specific cellular immune responses were observed in 5 of the 15 patients (33%). A transient decrease in circulating levels of HCV RNA, from −0.52 log10 to −1.24 log10, was observed in 8 patients; in 5 patients, the lowest level of HCV RNA was observed on day 37, after the first injection. The most pronounced decrease in viral load occurred in 2 patients, who also had marked vaccine-induced T-cell responses.

Conclusions

In patients with CHC, the viral-vector–based vaccine TG4040 had a good safety profile, induced HCV-specific cellular immune responses, and reduced viral load. This vaccine should be investigated in further clinical studies, in combination with standard of care.

Section snippets

Study Design

The study was conducted in full accordance with the 1996 Declaration of Helsinski and Good Clinical Practice with approval from the ethical review committee (Comité de Protection des Personnes) of Lyon (France). All patients provided written informed consent before participating in any study-related activity (The trial is referenced in ClinicalTrials.gov; under the identifier: NCT00529321).

This study was a multicenter, open-label, dose escalation study. TG4040 was administered subcutaneously at

Results

A total of 15 patients was enrolled in the study. The first 9 patients were sequentially treated in 3 cohorts (Figure 1). Each cohort consisted of 3 patients receiving 3 subcutaneous injections of TG4040 on days 1, 8, and 15 at a dose of either 106, 107, or 108 PFU depending on their inclusion in cohort 1, 2, or 3 respectively. All patients were followed up to at least 6 months after the first injection. Patients treated at the 108 PFU dose received a TG4040 boost injection at the same dose, 6

Discussion

In this study, we report for the first time the clinical evaluation of a vector-based T-cell inducing vaccine for the treatment of CHC. The primary end point of the study was reached because TG4040 was shown to be safe at all doses tested. We did not observe any significant flares of hepatitis. Specifically, the only related TG4040 increase seen was transient and remained below 4 times the upper limit of the normal. Most of the reported AEs were typical of poxvirus-based vaccination, ie,

Acknowledgments

The authors thank Dr C. Brandt and Professor P. Bousquet from the Centre d'Investigation Clinique-Inserm 2, University Hospital Strasbourg, for their assistance in the conduct of this study; Professor Nicolas Meyer from the service de Santé Publique, University Hospital Strasbourg, for helpful discussions; B. Marie Bastien, C. Zemmour, and C. Ezzode for statistical input; and T. Nguyen for technical advice.

The corresponding authors had full access to all of the data and take full responsibility

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    Conflicts of interest These authors disclose the following: Christine Bain, Jean-Yves Bonnefoy, Geneviève Inchauspé, Géraldine Honnet, Delphine Agathon, Martin Baudin, Jean-Marc Limacher, and Myew-Ling Toh are employees of Transgene. The remaining authors disclose no conflicts.

    Funding Supported by Transgene, Strasbourg, France, and Biotherapic Grant from French Ministry of Research and Industry sponsored by Lyon Biopôle, France.

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