{"id":5414,"date":"2019-09-11T16:20:09","date_gmt":"2019-09-11T14:20:09","guid":{"rendered":"https:\/\/www.resist-cluster.de\/?page_id=5414"},"modified":"2026-01-02T11:39:36","modified_gmt":"2026-01-02T10:39:36","slug":"project-b10","status":"publish","type":"page","link":"https:\/\/www.resist-cluster.de\/en\/research\/project-area-b\/project-b10\/","title":{"rendered":"Project B10"},"content":{"rendered":"

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Which immune response is particularly efficient and can contribute to the development of a new vaccine?<\/h1><\/div>

Prof. Pietschmann\u00a0 |\u00a0 Prof. Krey\u00a0 |\u00a0 Prof. Cornberg\u00a0 |\u00a0 Prof. McHardy<\/a><\/p><\/h2><\/div>

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What is this research project about?<\/h1><\/div>
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Virus hepatitis: Model of a hepatitis C virus<\/p>\n<\/div>

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What is this research project about?<\/h1><\/div>

Hepatitis C virus (HCV) has chronically infected ca. 71 million people worldwide. These patients are at risk of severe liver disease including hepatocellular carcinoma. The WHO has reported approximately 400.000 HCV-associated deaths for 2015. Novel HCV combination therapies cure more than 95% of treated patients. However, many people are unaware of their infection, and high treatment costs limit access to therapy. In addition, successful therapy does not protect from viral re-infection, which occurs readily in populations with frequent virus exposure (e.g. people who inject drugs). For these reasons HCV transmission remains high and consequently development of a prophylactic HCV vaccine is an unmet medical need. In fact, recent studies suggest that global control of HCV will only be possible with a prophylactic HCV vaccine combined with antiviral treatment.<\/p>\n<\/div>

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What\u2019s the current status?<\/h1><\/div>
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The quality of the cellular immunity has an important influence on the clinical outcome of HCV infection. Moreover, accumulating evidence underpins the key role of broadly neutralizing antibodies (bnAbs) in the control of acute and chronic HCV infection. Notably, 20-30% of exposed individuals naturally clear the infection and immunization with recombinant glycoproteins elicits neutralizing antibodies in animal models. These findings raise hopes that development of a prophylactic HCV vaccine is possible.<\/p>\n

The HCV surface proteins E1 and E2 are the major targets for bnAbs and therefore in the focus of vaccine research. However, HCV has evolved a number of evasion mechanisms, which complicate development of E1-E2-directed vaccines: Extensive sugar modifications of E1 and E2, and flexibility of key antibody target sites reduce immunogenicity. Moreover, most antibodies are directed against highly variable viral \u201cdecoy\u201d target sites, which readily mutate, rendering these antibodies ineffective.<\/p>\n<\/div>

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Concept of the HCV vaccine project: The Identi\ufb01kation of \u201cElite\u201d neutralizers \u2013 HCV patients who eliminate an infection or have a low viral load \u2013 is being translated into innovative vaccine approaches.<\/p>\n<\/div>

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What are the project goals?<\/h1><\/div>

Informed vaccine design requires in-depth understanding of the key target sites (epitopes) recognized by potent neutralizing antibodies. However, we know relatively little about the evolution of HCV bnAbs in humans, about the epitopes they target and the maturation pathways that B cells undergo to produce them. Therefore, our key aim will be the identification of individuals with a particularly efficient antibody response to HCV (so called \u201celite\u201d neutralizers). A detailed characterization of unique and powerful bnAbs from these patients will reveal a footprint of an efficient HCV-specific antibody response. It will reveal key characteristics required for evolution of potent neutralizing antibodies and will serve as gold standard guiding vaccine development. Based on these novel insights we will create vaccine candidates applying recently emerging methods of structure-based immunogen design to elicit such a bnAb response upon immunization.<\/p>\n<\/div><\/div><\/div>

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How do we get there?<\/h1><\/div>
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A paramount step in this project will be the identification of such \u201celite\u201d neutralizers from the patients treated in the MHH hepatitis outpatient clinic by performing a large-scale neutralization screening. In order to identify these patients with a particularly efficient immune response, the project uses the hepatitis C cohort of the MHH. This screening will identify elite neutralizers as well as patients with moderate or weak antibody responses. Consequently, it will enable molecular analyses of the determinants that control evolution of powerful antibodies. To this end, we will use single cell-resolved B cell profiling in these different patient groups to investigate differences in the B cell repertoires that correlate with evolution of phenotypically distinct antibody responses. To identify potent HCV-specific bnAbs, we will isolate B cells from elite neutralizers. Subsequently, we will sequence and clone B cell receptor genes. We will measure neutralization potency and will functionally and structurally analyze antibody-antigen complexes for the most powerful antibodies. This work should provide detailed structural information on neutralization epitopes and antigen recognition by potent bnAbs. It will pave the way for the use of novel computational methods for immunogen design using structure-based strategies with the primary goal to optimize immunogenic epitope presentation for enhanced induction of epitope-specific antibodies.<\/p>\n<\/div>

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Projectleaders<\/h1><\/div>

Project title: HCV vaccine<\/h4><\/div>
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Prof. Dr. Thomas Pietschmann<\/h3><\/div>

Projects: A1<\/a>, B10<\/a><\/h3><\/div>
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CV & VIDEO<\/span><\/a><\/div>
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Prof. Dr. Thomas Krey<\/h3><\/div>

Projects: B10<\/a>, D1<\/a>, D2<\/a><\/h3><\/div>
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CV & Contact<\/span><\/a><\/div>
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Prof. Dr. Markus Cornberg<\/h3><\/div>

Projects: B8<\/a>, B9<\/a>, B10<\/a><\/h3><\/div>
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CV & VIDEO<\/span><\/a><\/div>
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Prof. Dr. Alice McHardy<\/h3><\/div>

Projects: B2<\/a>, B10<\/a>, C1<\/a><\/h3><\/div>
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CV & VIDEO<\/span><\/a><\/div>
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Project B10 Publications<\/h1><\/div>

Publikationen 2025<\/strong><\/p>\n

Transient interferon-driven NK cell activation in acute hepatitis C<\/strong><\/a> B. Strunz, Q. Zhan, T. Khera, J. Hengst, M. Jankovic, K. Deterding, et al. J Infect Dis<\/strong> 2025 Accession Number: 41453396 DOI: 10.1093\/infdis\/jiaf654<\/p>\n

Impact of distinct antiviral treatment regimens on the long-term outcome after HCV cure – Data from the German Hepatitis C-Registry (DHC-R)<\/strong><\/a> V. Ohlendorf, Y. Serfert, P. Buggisch, S. Mauss, H. Klinker, G. Teuber, et al. Z Gastroenterol<\/strong> 2025 Vol. 63 Issue 5 Pages 486-496 Accession Number: 40360141 DOI: 10.1055\/a-2543-5205<\/p>\n

Distinct Inflammatory Imprint in Non-Cirrhotic and Cirrhotic Patients Before and After Direct-Acting Antiviral Therapy<\/strong><\/a> M. Witte, C. Oltmanns, J. Tauwaldt, H. Schmaus, J. Mischke, G. Grabert, et al. Clin Mol Hepatol<\/strong> 2025 Accession Number: 40462644 DOI: 10.3350\/cmh.2025.0292<\/p>\n

Publikationen 2024<\/strong><\/p>\n

Epitope-focused immunogens targeting the hepatitis C virus glycoproteins induce broadly neutralizing antibodies<\/strong><\/a> K. Nagarathinam, A. Scheck, M. Labuhn, L. J. Str\u00f6h, E. Herold, B. Veselkova, et al. Sci Adv 2024<\/strong> Vol. 10 Issue 49 Pages eado2600 Accession Number: 39642219 PMCID: PMC11623273 DOI: 10.1126\/sciadv.ado2600<\/p>\n

Impending HCC diagnosis in patients with cirrhosis after HCV cure features a natural killer cell signature<\/strong><\/a> S. A. Engelskircher, P. C. Chen, B. Strunz, C. Oltmanns, T. Ristic, S. Owusu Sekyere, et al. Hepatology 2024<\/strong> Vol. 80 Issue 1 Pages 202-222 Accession Number: 38381525 PMCID: PMC11191062 DOI: 10.1097\/hep.0000000000000804<\/p>\n

Unraveling the dynamics of hepatitis C virus adaptive mutations and their impact on antiviral responses in primary human hepatocytes.\u00a0<\/b><\/a>Frericks N, Brown RJP, Reinecke BM, Herrmann M, Br\u00fcggemann Y, Todt D, Miskey C, Vondran FWR, Steinmann E, Pietschmann T, Sheldon J. J Virol<\/strong>. 2024 Feb 6:e0192123. doi: 10.1128\/jvi.01921-23. Online ahead of print. PMID: 38319104<\/p>\n

Elevation of S2-bound \u03b11-acid glycoprotein is associated with chronic hepatitis C virus infection and hepatocellular carcinoma<\/b><\/a>. Oltmanns, C., B. Bremer, L. Kusche, P. St\u00e5l, R. Zenlander, J. Tauwaldt, I. Ryd\u00e9n, P. P\u00e5hlsson, M. Cornberg, and H. Wedemeyer. 2024. J Viral Hepat<\/strong>.<\/p>\n

Publikationen 2023<\/strong><\/p>\n

Proteomics reveals a global phenotypic shift of NK cells in HCV patients treated with direct-acting antivirals.<\/strong> <\/a>Bi W, Kraft A, Engelskircher S, Mischke J, Witte M, Klawonn F, van Ham M, Cornberg M, Wedemeyer H, Hengst J, J\u00e4nsch L. Eur J Immunol<\/strong>. 2023 Jul 29:e2250291.<\/p>\n

Structural insights into hepatitis C virus neutralization.<\/strong>\u00a0<\/a>Str\u00f6h LJ, Krey T.\u00a0 Curr Opin Virol<\/strong>. 2023 Mar 29;60:101316.<\/p>\n

Immunological scars after cure of hepatitis C virus infection: Long-HepC?<\/strong><\/a>\u00a0Cornberg M, Mischke J, Kraft AR, Wedemeyer H. Curr Opin Immunol<\/strong>. 2023 Apr 10;82:102324.<\/p>\n

Controlled Attenuation Parameter Is Associated with a Distinct Systemic Inflammatory Milieu after Clearance of HCV Infection.<\/strong><\/a>\u00a0Du Y, Khera T, Liu Z, Tudrujek-Zdunek M, Dworzanska A, Cornberg M, Xu CJ, Tomasiewicz K, Wedemeyer H.\u00a0 Biomedicines<\/strong>. 2023 May 25;11(6):1529. doi: 10.3390\/biomedicines11061529. PMID: 37371624; PMCID: PMC10295384.<\/p>\n

Publikationen 2022
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Development approaches for vaccines against hepatitis C virus infections.<\/strong><\/a>\u00a0Bankwitz D, Krey T, Pietschmann T.\u00a0 Bundesgesundheitsblatt Gesundheitsforschung Gesundheitsschutz<\/strong>. 2022 Feb;65(2):183-191. German. doi: 10.1007\/s00103-021-03477-9. Epub 2022 Jan 11. PMID: 35015104; PMCID: PMC8749110.<\/p>\n

Analysis of antibodies from HCV elite neutralizers identifies genetic determinants of broad neutralization<\/a>.<\/strong> Weber T, Potthoff J, Bizu S, Labuhn M, Dold L, Schoofs T, Horning M, Ercanoglu MS, Kreer C, Gieselmann L, Vanshylla K, Langhans B, Janicki H, Str\u00f6h LJ, Knops E, Nierhoff D, Spengler U, Kaiser R, Bjorkman PJ, Krey T, Bankwitz D, Pfeifer N, Pietschmann T, Flyak AI, Klein F. Immunity<\/strong>.<\/p>\n

The Human Liver-Expressed Lectin CD302 Restricts Hepatitis C Virus Infection.\u00a0<\/strong><\/a>Reinecke B, Frericks N, Lauber C, Dinkelborg K, Matthaei A, Vondran FWR, Behrendt P, Haid S, Brown RJP, Pietschmann T. J Virol<\/strong>.<\/p>\n

A Hepatitis C virus genotype 1b post-transplant isolate with high replication efficiency in cell culture and its adaptation to infectious virus production in vitro and in vivo.<\/strong>\u00a0<\/a>Heuss C, Rothhaar P, Burm R, Lee JY, Ralfs P, Haselmann U, Str\u00f6h LJ, Colasanti O, Tran CS, Sch\u00e4fer N, Schnitzler P, Merle U, Bartenschlager R, Patel AH, Graw F, Krey T, Laketa V, Meuleman P, Lohmann V. PLoS Pathog<\/strong>.<\/p>\n

An Equine Model for Vaccination against a Hepacivirus: Insights into Host Responses to E2 Recombinant Protein Vaccination and Subsequent Equine Hepacivirus Inoculation<\/strong><\/a> M. Badenhorst, A. Saalm\u00fcller, J. M. Daly, R. Ertl, M. Stadler, C. Puff, et al. Viruses<\/strong> 2022 Vol. 14 Issue 7 Pages 1401 DOI: 10.3390\/v14071401<\/p>\n

Metamizole-Associated Risks in Decompensated Hepatic Cirrhosis<\/strong><\/a> B. Schulte, T. L. Tergast, M. Griemsmann, D. Menti, N. Deveci, J. Kahlh\u00f6fer, et al. Dtsch Arztebl Int<\/strong> 2022 Vol. 119 Issue 41 Pages 687-693 Accession Number: 35912424 PMCID: PMC9830680 DOI: 10.3238\/arztebl.m2022.0280<\/p>\n

Publikationen 2021<\/strong><\/p>\n

Initial HCV infection of adult hepatocytes triggers a temporally structured transcriptional program containing diverse pro- and anti-viral elements<\/a><\/strong> B. Tegtmeyer, G. Vieyres, D. Todt, C. Lauber, C. Ginkel, M. Engelmann, et al. Journal of Virology<\/strong> 2021 DOI: 10.1128\/JVI.00245-21<\/p>\n

EpitopeVec: Linear Epitope Prediction Using Deep Protein Sequence Embeddings. <\/strong><\/a>Bioinformatics.<\/strong>Bahai A, Asgari E, Mofrad MRK, Kloetgen A, McHardy AC.<\/p>\n

Hepatitis C reference viruses highlight potent antibody responses and diverse viral functional interactions with neutralising antibodies.<\/a><\/strong> Bankwitz D, Bahai A, Labuhn M, Doepke M, Ginkel C, Khera T, Todt D, Str\u00f6h LJ, Dold L, Klein F, Klawonn F, Krey T, Behrendt P, Cornberg M, McHardy AC, Pietschmann T. Gut<\/strong>. 2020<\/p>\n

Publikationen 2020<\/strong><\/p>\n

Liver-expressed Cd302 and Cr1l limit hepatitis C virus cross-species transmission to mice.<\/a><\/strong> Brown RJP, Tegtmeyer B, Sheldon J, Khera T, Anggakusuma, Todt D, Vieyres G, Weller R, Joecks S, Zhang Y, Sake S, Bankwitz D, Welsch K, Ginkel C, Engelmann M, Gerold G, Steinmann E, Yuan Q, Ott M, Vondran FWR, Krey T, Str\u00f6h LJ, Miskey C, Ivics Z, Herder V, Baumg\u00e4rtner W, Lauber C, Seifert M, Tarr AW, McClure CP, Randall G, Baktash Y, Ploss A, Thi VLD, Michailidis E, Saeed M, Verhoye L, Meuleman P, Goedecke N, Wirth D, Rice CM, Pietschmann Sci Adv<\/strong>.<\/p>\n

HCV Glycoprotein Structure and Implications for B-Cell Vaccine Development<\/a>.<\/strong> Str\u00f6h LJ, Krey T. Int J Mol Sci<\/strong>.<\/p>\n

Global and local envelope protein dynamics of hepatitis C virus determine broad antibody sensitivity<\/strong><\/a>.<\/strong> Augestad EH, Castelli M, Clementi N, Str\u00f6h LJ, Krey T, Burioni R, Mancini N, Bukh J, Prentoe J. Sci Adv<\/strong>.<\/p>\n

De novo protein design enables the precise induction of RSV-neutralizing antibodies.<\/a>\u00a0<\/strong>Sesterhenn F, Yang C, Bonet J, Cramer JT, Wen X, Wang Y, Chiang CI, Abriata LA, Kucharska I, Castoro G, Vollers SS, Galloux M, Dheilly E, Rosset S, Corth\u00e9sy P, Georgeon S, Villard M, Richard CA, Descamps D, Delgado T, Oricchio E, Rameix-Welti MA, M\u00e1s V, Ervin S, El\u00e9ou\u00ebt JF, Riffault S, Bates JT, Julien JP, Li Y, Jardetzky T, Krey T, Correia BE. Science<\/strong>.<\/p>\n

Efficient acute and chronic infection of stem cell-derived hepatocytes by hepatitis C virus<\/a><\/strong>. Carpentier A, Sheldon J, Vondran FWR, Brown RJ, Pietschmann T. Gut<\/strong>.<\/p>\n<\/div>

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Publications of the Project B10<\/h1><\/div>
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