- Email: [email protected]
O.101 A novel primboost therapeutic vaccine induces sustained seroconversion at 52 weeks in patients with HBeAg+ chronic hepatitis B: A phase IIa clinical trial
$30
Journal of Clinical Virology 2006, Vol 36 (suppl 2)
I - O - _ ~ A novel primeboost therapeutic vaccine induces sustained seroconversion at 52 weeks in patients with HBeAg+ chronic hepatitis B: a phase Ila clinical trial J. Schneider 1 *, W. Halota 2, D. Delic 3, Z. Nesic 3, D. Prokopowicz4, R. Flisiak4, J. Kuydowicz 5, M. Jablkowski 5, J. Cianciara 6, T. Mach 7, R. Modrzewska 8, M. Fabri 9, D. Tomic 3, A. Horban 1°, W. Krycka 11, M. Cripps 1. l Oxxon Therapeutics Ltd, Oxford, United Kingdom,
2Nicolaus Copernicus University, Bydgoszcz, Poland, 3Clinical Centre of Serbia, Belgrade, Serbia, 4Medical University of Bialystok, Bialystok, 5Bieganskiego Hospital, Lodz, 61nstitute of Infectious and Parasitic Diseases, Warsaw; 7University Hospital, Krakow; 8 Medical University of Lublin, Lublin, Poland, 9Clinical Centre Novi Sad, Novi Sad, Serbia, 10Warsaw Medical University, Warsaw; 11Principal Hospital, Kielce, Poland Background and Objectives: Resolution of HBV infection has been associated with HBV-specific immune responses. An immunotherapeutic capable of inducing HBV-specific T cell responses could offer an effective HBV treatment. Here we report the results of a randomized controlled phase Ila study investigating a diseasespecific therapeutic vaccine for the treatment of chronic Hepatitis B. Methods: 54 HBeAg+ patients were randomized to receive either therapeutic vaccine alone, therapeutic vaccine plus lamivudine or lamivudine alone. The vaccine, given at three-week intervals, comprised two DNA plasmid "primes" (2 rag) and two modified vaccinia virus Ankara (MVA) "boosts" (5 • Oe8pfu), both vectors expressing the same HBV surface antigen. T cell responses were assessed using ex vivo Interferon (IFN) gamma ELISPOT assays. Plasma HBVDNA viral load was assessed using PCR. Results: In total 20/53 patients studied showed ex vivo IFNgamma; ELISPOT responses potentially related to the treatment, however these responses were of very low frequency. The most common treatment related adverse events were injection site reactions (39%), and aminotransferase elevations (11%). Five patients reported serious adverse events, two of which were treatment related (aminotransferase elevations. HBeAg loss, seroconversion rates and HBV viral load responses are summarized in table.
HBeAg loss (any time) HBe seroconversion (any time) Seroconversion (wk 52) HBVDNA< 105 cp/ml (wk 52)
Vaccine (n = 21)
Vaccine + Lamivudine a (n = 22)
Lamivudine a (n = 11)
8 5 4 4
3 (14%) 1(5%) 1(5%) 3 (14%)
1 (9%) 0 0 0
(38%) (24%) (19%) (19%)
aLamivudine treatment for initial 14 weeks only.
Conclusion: This is the first demonstration of sustained HBe seroconversion with this novel disease-specific therapeutic vaccine in a randomized-controlled trial. The vaccine was well tolerated and appears capable of inducing HBe antigen clearance and seroconversion in patients with chronic Hepatitis B. This data supports further evaluation in a larger trial. I-~-~
Combination therapy with entecavir and "prime-boost" vaccines prevents the development of chronic duck hepatitis B virus infection
D.S. Miller 1, D. Boyle2, I. Kotlarski 3, R. Colonno 4, A.R. Jilbert 5..
1School of Molecular Biomedical Science, University of Adelaide, Adelaide; 2Australian Animal Health Laboratory, CSIRO, Geelong; 3School Molecular Biomedical Science, University of Adelaide, Adelaide, Australia, 4 Virology Drug Discovery, Bristol-Myers Squibb Pharmaceutical Research, Wallingford, USA, 5Infectious Diseases Laboratories, Institute of Medical and Veterinary Science, Adelaide, Australia Background and Objectives: As a first step in developing improved therapeutic strategies for chronic hepadnavirus infections, we have explored ways to induce immune responses that target infected cells and prevent the development of chronic infection. We previously reported that -50% of ducks infected with a high-dose of duck hepatitis B virus (DHBV) and simultaneously treated with the nucleoside analogue entecavir (ETV), resolved the infection, while 100% of untreated ducks developed chronic infection (Foster et al.,
Abstracts, 12th ISHVLD 2005. J.Virol 79:5819-32). To further reduce the incidence of chronic DHBV infection, ETV treatment was combined with injection of DNA vaccines to "prime", and inoculation of recombinant fowlpoxviruses (FPV) to "boost", an antiviral immune response. Methods: FPV strains expressing the DHBV envelope and core antigens were derived from the vaccine strain, FPV-M3. In an initial study, 20, 14-day-old ducks were infected with 5 . 1 0 8 DHBV genomes. Simultaneously, 10 of the ducks were injected with plasmid DNA vaccines expressing the DHBV envelope and core proteins and, one week later, were inoculated with the recombinant FPV-M3 strains that expressed the same DHBV proteins. The other 10 ducks received vector control plasmids and FPV-M3. Five ducks from each group also received ETV (1.0 mg/kg/day) from the time of DHBV infection for 14 days. Liver tissue was collected on days 4, 14 and 67 post-inoculation (pi). Results: Results and Conclusion. DHBV-infected hepatocytes were observed in the liver of all ducks at day 4 pi, though fewer were observed in those treated with ETV then in the comparable untreated group. By day 14, 5/5 ducks that received ETV in combination with "prime-boost" vaccination had no detectable DHBV-infected cells. Analysis of autopsy tissue collected at day 67 pi from this study and two follow up studies showed that ETV treatment and "prime-boost" vaccination stimulated immune responses that enabled resolution of DHBV infection in 15/15 ducks. "Prime boost" vaccination alone prevented chronic infection in 1/5 ducks. ETV treatment alone, and in combination with the control vaccines, prevented chronic infection in 7/15 ducks. All non-ETV treated and vaccine control ducks (10/10) developed chronic DHBV infection. Conclusion: ETV treatment in combination with DNA vaccine priming and rFPV boosting of the immune response enabled resolution and prevented the development of chronic DHBV infection.
[-~-~
Combination therapy with antiviral drugs and immunomodulation against chronic hepatitis B virus infection: evaluation in the woodchuck model
M. Lu 1 *, X. Yao2, Y. Xu 1, H. Lorenz 3, U. Dahmen 4, H. Chi 4, O. Dirsch 5, T. Kemper 1, L. He 2, D. Glebe 3, W. Gerlich 3, Y. Wen 2, M. Roggendorf 1. 1Institute of Virology, University Hospital of
Essen, Essen, Germany, 2Dept. of Molecular Virology, Medical Center of Fudan University, Shanghai, China, 3Institute of Medical Virology, Justus-Leibig-University of Giessen, Giessen; 4Klinik fuer AIIgemeine Viszeral und Transplantationschirugie, Univesitaetsklinikum Essen, Essen, 51nstitut fuer Pathologic, Universitaetsklinkum Koeln, Koeln, Germany Background and Objectives: Therapeutic vaccinations are considered as an attractive approach for treatment of chronic hepatitis B virus (HBV) infection. Yet, the results from clinical trials and experiments in animal models indicated that the current protocols are not optimal. It becomes generally accepted that an multimodal immune response including T- and B-cell responses is essential to control HBV infection. Thus, a multimodal therapeutic strategy including antiviral treatment and simultaneous stimulation of specific T- and B-cells is warranted. A combination of antiviral treatment with lamivudine and therapeutic vaccination with DNA vaccines or/and antigen-antibody immune complexes (IC) was carried out in the woodchuck model to evaluate their efficacy. Methods: Two prototype vaccines, DNA vaccines and IC, were used. Ten woodchucks with chronic woodchuck hepatitis virus (WHV) infection were treated with 15mg of lamivudine/day for 4 months. 6 weeks after the starting of lamivudine treatment, woodchucks were immunized with DNA vaccines (n =4) or with WHsAganti-WHs IC and DNA vaccines (n = 4). Two woodchucks treated with lamivudine only served as controls. WHV DNA, serum WHsAg concentration, anti-WHs antibody, and lymphoproliferative responses to WHV antigens in these woodchucks were moniotored. Liver samples were taken at the end of treatment to assess pathological changes. Results: The treatment with lamivudine led to a slight decrease of WHV DNA concentrations in woodchucks. Immunizations with DNA vaccines alone led to a significant reduction of WHV DNA and serum WHsAg concentrations only in one of 4 woodchucks. All 4 woodchucks immunized with DNA and IC developed anti-WHs and showed a further decrease of serum WHV DNA concentrations to 3
Journal of Clinical Virology 2006, Vol 36 (suppl 2)
I - O - _ ~ A novel primeboost therapeutic vaccine induces sustained seroconversion at 52 weeks in patients with HBeAg+ chronic hepatitis B: a phase Ila clinical trial J. Schneider 1 *, W. Halota 2, D. Delic 3, Z. Nesic 3, D. Prokopowicz4, R. Flisiak4, J. Kuydowicz 5, M. Jablkowski 5, J. Cianciara 6, T. Mach 7, R. Modrzewska 8, M. Fabri 9, D. Tomic 3, A. Horban 1°, W. Krycka 11, M. Cripps 1. l Oxxon Therapeutics Ltd, Oxford, United Kingdom,
2Nicolaus Copernicus University, Bydgoszcz, Poland, 3Clinical Centre of Serbia, Belgrade, Serbia, 4Medical University of Bialystok, Bialystok, 5Bieganskiego Hospital, Lodz, 61nstitute of Infectious and Parasitic Diseases, Warsaw; 7University Hospital, Krakow; 8 Medical University of Lublin, Lublin, Poland, 9Clinical Centre Novi Sad, Novi Sad, Serbia, 10Warsaw Medical University, Warsaw; 11Principal Hospital, Kielce, Poland Background and Objectives: Resolution of HBV infection has been associated with HBV-specific immune responses. An immunotherapeutic capable of inducing HBV-specific T cell responses could offer an effective HBV treatment. Here we report the results of a randomized controlled phase Ila study investigating a diseasespecific therapeutic vaccine for the treatment of chronic Hepatitis B. Methods: 54 HBeAg+ patients were randomized to receive either therapeutic vaccine alone, therapeutic vaccine plus lamivudine or lamivudine alone. The vaccine, given at three-week intervals, comprised two DNA plasmid "primes" (2 rag) and two modified vaccinia virus Ankara (MVA) "boosts" (5 • Oe8pfu), both vectors expressing the same HBV surface antigen. T cell responses were assessed using ex vivo Interferon (IFN) gamma ELISPOT assays. Plasma HBVDNA viral load was assessed using PCR. Results: In total 20/53 patients studied showed ex vivo IFNgamma; ELISPOT responses potentially related to the treatment, however these responses were of very low frequency. The most common treatment related adverse events were injection site reactions (39%), and aminotransferase elevations (11%). Five patients reported serious adverse events, two of which were treatment related (aminotransferase elevations. HBeAg loss, seroconversion rates and HBV viral load responses are summarized in table.
HBeAg loss (any time) HBe seroconversion (any time) Seroconversion (wk 52) HBVDNA< 105 cp/ml (wk 52)
Vaccine (n = 21)
Vaccine + Lamivudine a (n = 22)
Lamivudine a (n = 11)
8 5 4 4
3 (14%) 1(5%) 1(5%) 3 (14%)
1 (9%) 0 0 0
(38%) (24%) (19%) (19%)
aLamivudine treatment for initial 14 weeks only.
Conclusion: This is the first demonstration of sustained HBe seroconversion with this novel disease-specific therapeutic vaccine in a randomized-controlled trial. The vaccine was well tolerated and appears capable of inducing HBe antigen clearance and seroconversion in patients with chronic Hepatitis B. This data supports further evaluation in a larger trial. I-~-~
Combination therapy with entecavir and "prime-boost" vaccines prevents the development of chronic duck hepatitis B virus infection
D.S. Miller 1, D. Boyle2, I. Kotlarski 3, R. Colonno 4, A.R. Jilbert 5..
1School of Molecular Biomedical Science, University of Adelaide, Adelaide; 2Australian Animal Health Laboratory, CSIRO, Geelong; 3School Molecular Biomedical Science, University of Adelaide, Adelaide, Australia, 4 Virology Drug Discovery, Bristol-Myers Squibb Pharmaceutical Research, Wallingford, USA, 5Infectious Diseases Laboratories, Institute of Medical and Veterinary Science, Adelaide, Australia Background and Objectives: As a first step in developing improved therapeutic strategies for chronic hepadnavirus infections, we have explored ways to induce immune responses that target infected cells and prevent the development of chronic infection. We previously reported that -50% of ducks infected with a high-dose of duck hepatitis B virus (DHBV) and simultaneously treated with the nucleoside analogue entecavir (ETV), resolved the infection, while 100% of untreated ducks developed chronic infection (Foster et al.,
Abstracts, 12th ISHVLD 2005. J.Virol 79:5819-32). To further reduce the incidence of chronic DHBV infection, ETV treatment was combined with injection of DNA vaccines to "prime", and inoculation of recombinant fowlpoxviruses (FPV) to "boost", an antiviral immune response. Methods: FPV strains expressing the DHBV envelope and core antigens were derived from the vaccine strain, FPV-M3. In an initial study, 20, 14-day-old ducks were infected with 5 . 1 0 8 DHBV genomes. Simultaneously, 10 of the ducks were injected with plasmid DNA vaccines expressing the DHBV envelope and core proteins and, one week later, were inoculated with the recombinant FPV-M3 strains that expressed the same DHBV proteins. The other 10 ducks received vector control plasmids and FPV-M3. Five ducks from each group also received ETV (1.0 mg/kg/day) from the time of DHBV infection for 14 days. Liver tissue was collected on days 4, 14 and 67 post-inoculation (pi). Results: Results and Conclusion. DHBV-infected hepatocytes were observed in the liver of all ducks at day 4 pi, though fewer were observed in those treated with ETV then in the comparable untreated group. By day 14, 5/5 ducks that received ETV in combination with "prime-boost" vaccination had no detectable DHBV-infected cells. Analysis of autopsy tissue collected at day 67 pi from this study and two follow up studies showed that ETV treatment and "prime-boost" vaccination stimulated immune responses that enabled resolution of DHBV infection in 15/15 ducks. "Prime boost" vaccination alone prevented chronic infection in 1/5 ducks. ETV treatment alone, and in combination with the control vaccines, prevented chronic infection in 7/15 ducks. All non-ETV treated and vaccine control ducks (10/10) developed chronic DHBV infection. Conclusion: ETV treatment in combination with DNA vaccine priming and rFPV boosting of the immune response enabled resolution and prevented the development of chronic DHBV infection.
[-~-~
Combination therapy with antiviral drugs and immunomodulation against chronic hepatitis B virus infection: evaluation in the woodchuck model
M. Lu 1 *, X. Yao2, Y. Xu 1, H. Lorenz 3, U. Dahmen 4, H. Chi 4, O. Dirsch 5, T. Kemper 1, L. He 2, D. Glebe 3, W. Gerlich 3, Y. Wen 2, M. Roggendorf 1. 1Institute of Virology, University Hospital of
Essen, Essen, Germany, 2Dept. of Molecular Virology, Medical Center of Fudan University, Shanghai, China, 3Institute of Medical Virology, Justus-Leibig-University of Giessen, Giessen; 4Klinik fuer AIIgemeine Viszeral und Transplantationschirugie, Univesitaetsklinikum Essen, Essen, 51nstitut fuer Pathologic, Universitaetsklinkum Koeln, Koeln, Germany Background and Objectives: Therapeutic vaccinations are considered as an attractive approach for treatment of chronic hepatitis B virus (HBV) infection. Yet, the results from clinical trials and experiments in animal models indicated that the current protocols are not optimal. It becomes generally accepted that an multimodal immune response including T- and B-cell responses is essential to control HBV infection. Thus, a multimodal therapeutic strategy including antiviral treatment and simultaneous stimulation of specific T- and B-cells is warranted. A combination of antiviral treatment with lamivudine and therapeutic vaccination with DNA vaccines or/and antigen-antibody immune complexes (IC) was carried out in the woodchuck model to evaluate their efficacy. Methods: Two prototype vaccines, DNA vaccines and IC, were used. Ten woodchucks with chronic woodchuck hepatitis virus (WHV) infection were treated with 15mg of lamivudine/day for 4 months. 6 weeks after the starting of lamivudine treatment, woodchucks were immunized with DNA vaccines (n =4) or with WHsAganti-WHs IC and DNA vaccines (n = 4). Two woodchucks treated with lamivudine only served as controls. WHV DNA, serum WHsAg concentration, anti-WHs antibody, and lymphoproliferative responses to WHV antigens in these woodchucks were moniotored. Liver samples were taken at the end of treatment to assess pathological changes. Results: The treatment with lamivudine led to a slight decrease of WHV DNA concentrations in woodchucks. Immunizations with DNA vaccines alone led to a significant reduction of WHV DNA and serum WHsAg concentrations only in one of 4 woodchucks. All 4 woodchucks immunized with DNA and IC developed anti-WHs and showed a further decrease of serum WHV DNA concentrations to 3