Sutter, G. (Gerd)
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- Vaccine-induced early control of hepatitis C virus infection in chimpanzees fails to impact on hepatic PD-1 and chronicity(Wiley-Blackwell, 2007) Riezu-Boj, J.I. (José Ignacio); Whelan, M. (Myke); Paranhos-Baccala, G. (Glaucia); Staib, C. (Caroline); Berland, J.L. (Jean-Luc); Bartosch, B. (Birke); Larrea, E. (Esther); Rollier, C.S. (Christine S.); Pape, G.R. (Gerd R.); Sutter, G. (Gerd); Fagrouch, Z. (Zahra); Verschoor, E.J. (Ernst J.); Duverger, B. (Blandine); Diepolder, H.M. (Helmut M.); Meyr, M. (Marcus); Cosset, F. L. (Francoise-L.); Verstrepen, B.E. (Babs E.); Komurian-Pradel, F. (Florence); Himoudi, N. (Nourredine); Spaan, W.J.M. (Willy J.M.); Adams, V.A. (Victoria A.); Whelan, J.A. (Joseph A.); Heeney, J.L. (Jonathan L.); Drexhage, J.A.R. (Joost A.R.); Inchauspe, G. (Geneviese); Lasarte, J.J. (Juan José)Broad T cell and B cell responses to multiple HCV antigens are observed early in individuals who control or clear HCV infection. The prevailing hypothesis has been that similar immune responses induced by prophylactic immunization would reduce acute virus replication and protect exposed individuals from chronic infection. Here, we demonstrate that immunization of naïve chimpanzees with a multicomponent HCV vaccine induced robust HCV-specific immune responses, and that all vaccinees exposed to heterologous chimpanzee-adapted HCV 1b J4 significantly reduced viral RNA in serum by 84%, and in liver by 99% as compared to controls (P=0.024 and 0.028, respectively). However, despite control of HCV in plasma and liver in the acute period, in the chronic phase, 3 of 4 vaccinated animals developed persistent infection. Analysis of expression levels of proinflammatory cytokines in serial hepatic biopsies failed to reveal an association with vaccine outcome. However, expression of IDO, CTLA-4 [corrected] and PD-1 levels in liver correlated with clearance or chronicity. CONCLUSION: Despite early control of virus load, a virus-associated tolerogenic-like state can develop in certain individuals independent of vaccination history.
- Protective vaccination with hepatitis C virus NS3 but not core antigen in a novel mouse challenge model(John Wiley and Sons, 2008) Staib, C. (Caroline); Sutter, G. (Gerd); Adler, H. (Heiko); El-Gogo, S. (Susanne); Lasarte, J.J. (Juan José)BACKGROUND: Efficient vaccines against hepatitis C virus (HCV) infection are urgently needed. Vaccine development has been hampered by the lack of suitable small animal models to reliably test the protective capacity of immmunization. METHODS: We used recombinant murine gammaherpesvirus 68 (MHV-68) as a novel challenge virus in mice and tested the efficacy of heterologous candidate human vaccines based on modified vaccinia virus Ankara or adenovirus, both delivering HCV non-structural NS3 or core proteins. RESULTS: Recombinant MHV-68 expressing NS3 (MHV-68-NS3) or core (MHV-68-core) were constructed and characterized in vitro and in vivo. Mice immunized with NS3-specific vector vaccines and challenged with MHV-68-NS3 were infected but showed significantly reduced viral loads in the acute and latent phase of infection. NS3-specific CD8+ T cells were amplified in immunized mice after challenge with MHV-68-NS3. By contrast, we did neither detect a reduction of viral load nor an induction of core-specific CD8+ T cells after core-specific immunization. CONCLUSIONS: Our data suggest that the challenge system using recombinant MHV-68 is a highly suitable model to test the immunogenicity and protective capacity of HCV candidate vaccine antigens. Using this system, we demonstrated the usefulness of NS3-specific immunization. By contrast, our analysis rather discarded core as a vaccine antigen.