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A FIRST CLINICAL TRIAL OF THERAPEUTIC VACCINATION USING NAKED DNA DELIVERED BY IN VIVO ELECTROPORATION SHOWS ANTIVIRAL EFFECTS IN PATIENTS WITH CHRONIC HEPATITIS C
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EASL 2009 April 23-26, 2009 Copenhagen, Denmark
Reported by Jules Levin
Matti Sallberg1, L. Frelin1, H. Diepolder2, M.-C. Jung3, I. Mathiesen4, M. Fons5, R. Hultcrantz6, T. Carlsson6, O. Weiland6
1Laboratory Medicine, Karolinska Institutet at Karolinska University Hospital Huddinge, Stockholm, Sweden, 2Medicine, Ludvig-Maximilian University, 3ImmuSystems GmbH, Munich, Germany, 4Inovio Biomedical, Oslo, Norway, 5Inovio Biomedical, San Diego, CA, USA, 6Medicine, Karolinska Institutet at Karolinska University Hospital, Stockholm, Sweden
Background: Clearance of HCV infection correlates with activation of the host T cell response. We developed a T cell vaccine based on a codon-optimized HCV non-structural (NS) 3/4A DNA-gene expressed under the control of the cytomegalovirus immediate-early promoter (ChronVac-C, Tripep AB, Sweden) delivered by in vivo electroporation (EP). A first phase I/IIa clinical trial in HCV infected patients is currently ongoing.
Methods: A volume of 0,5 mL saline containing ChronVac-C DNA was injected at 1 cm depth in the deltoid muscle. This was followed by two 60ms electrical pulses adminstered using a 1,5 cm four-electrode array (Medpulser DDS; Inovio, CA, US). Study aims were safety, immunogenicity, and effects on the viral load. Twelve treatment naive patients infected with HCV genotype 1 and a viral load < 800,000 IU/mL were divided in four groups of 167 µg, 500 µg, and 1,500 µg given as four monthly doses of DNA.
Results: In the 167µg group no severe side effects appeared, two mounted transient T cell responses, and none had a reduced viral load. In the 500µg dose no severe side effects appeared, and two developed better sustained HCV-specific T cell responses. Simultaneous with these responses both had reductions in the viral load of up to 0,89log10 and 1,5 log10, respectively. In the third patient no immune response developed and no clear reductions in the viral load were seen. In the 1,500µg dose no severe side effects appeared, and one developed HCV-specific T cell response. Two patients had reductions in the viral load of up to 1,2 log10 and 2,4 log10, respectively. Thus, four out of six (67%) patients in the two highest dose groups had reductions in the viral load exceeding 0,5log10 lasting for two to >10 weeks. Of these, three had activations of the HCV-specific T cell responses at the time of the reductions in the viral load.
Conclusions: These data provides the first proof-of-concept for DNA-based therapeutic vaccination against chronic hepatitis C in humans using in vivo electroporation and encourage further clinical development. The data also provides further evidence for the antiviral role of the HCV-specific T cell response.
First Evidence For DNA-based Vaccination Against Chronic Hepatitis C
ScienceDaily (Apr. 24, 2009) - The first-proof-of-concept for a DNA-based therapeutic vaccination against chronic hepatitis C was announced April 23 at EASL 2009, the Annual Meeting of the European Association for the Study of the Liver in Copenhagen, Denmark.
In the first clinical trial of a therapeutic vaccination using naked DNA delivered by in vivo electroporation (EP), antiviral effects were shown in patients with hepatitis C (HCV).
Researchers hope that this will encourage further clinical development. The data also provide further evidence for the antiviral role of the HCV-specific T cell response.
It is estimated that some 3% of the world's population is infected with HCV. In industrialised countries, hepatitis C accounts for 70% of chronic hepatitis cases. One of the main concerns is that HCV infection remains asymptomatic until advanced stages of the disease.
Clearance of HCV infection correlates with activation of the host T cell response. Therefore, in this study, researchers developed a T cell vaccine based on a codon-optimised HCV non-structural (NS) 3/4A DNA-gene expressed under the control of the cytomegalovirus immediate-early promoter (ChronVac-C) delivered by in vivo electroporation (EP). A first phase I/IIa clinical trial in HCV infected patients is currently ongoing.
Professor Matti Sallberg of Laboratory Medicine, the Karolinska Institutet, Stockholm, Sweden, who led the study, said: "In 50-80% of adult cases, the immune system fails to eliminate the HCV virus and the disease becomes chronic. Given that only about 50% of HCV infected persons are diagnosed in most developed countries and that two-thirds need to undergo antiviral treatment, this new vaccination has huge implications in terms of the future management of this widespread disease."
In this study, a volume of 0.5 ml saline containing ChronVac-C DNA was injected at 1 cm depth in the deltoid muscle. This was followed by two 60ms electrical pulses administered using a 1.5 cm four-electrode array (Medpulser DDS; Inovio, CA, US). The study aims were safety, immunogenicity, and effects on the viral load. Twelve treatment naive patients infected with HCV genotype 1 and a viral load <800,000 IU/ml were divided in four groups of 167 µg, 500 µg, and 1,500 µg given as four monthly doses of DNA.
In the 167µg group, no severe side effects were observed, two patients mounted transient T cell responses, and none had a reduced viral load. In the 500µg dose, no severe side effects were observed, and two developed better sustained HCV-specific T cell responses. Simultaneous with these responses, both patients had reductions in the viral load of up to 0.89 log10 and 1.5 log10, respectively. In the third patient, no immune response developed and no clear reductions in the viral load were seen. In the 1,500µg dose, no severe side effects were observed, and one patient developed HCV-specific T cell response. Two patients had reductions in the viral load of up to 1.2 log10 and 2.4 log10, respectively. Thus, 67% (four out of six) of patients in the two highest dose groups had reductions in the viral load exceeding 0.5 log10 lasting for two to >10 weeks. Of these, three had activations of the HCV-specific T cell responses at the time of the reductions in the viral load.
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