Epitope-focused immunogens targeting the hepatitis C virus glycoproteins induce broadly neutralizing antibodies
Hepatitis C virus (HCV) infection causes ~290,000 annual human deaths despite the highly effective antiviral treatment available. Several viral immune evasion mechanisms have hampered the development of an effective vaccine against HCV, among them the remarkable conformational flexibility within neutralization epitopes in the HCV antigens. Here, we report the design of epitope-focused immunogens displaying two distinct HCV cross-neutralization epitopes. We show that these immunogens induce a pronounced, broadly neutralizing antibody response in laboratory and transgenic human antibody mice. Monoclonal human antibodies isolated from immunized human antibody mice specifically recognized the grafted epitopes and neutralized four diverse HCV strains. Our results highlight a promising strategy for developing HCV immunogens and provide an encouraging paradigm for targeting structurally flexible epitopes to improve the induction of neutralizing antibodies.
Authors
- Maurice Labuhn
- Matthias Ballmaier (ORCID: https://orcid.org/0000-0002-1352-5995)
- Andreas Scheck (ORCID: https://orcid.org/0000-0002-2123-6499)
- Sarah Tune (ORCID: https://orcid.org/0000-0001-9022-9965)
- Michael Nassal (ORCID: https://orcid.org/0000-0003-2204-9158)
- Elisabeth Herold
- Thomas Krey (ORCID: https://orcid.org/0000-0002-4548-7241)
- Bruno E. Correia (ORCID: https://orcid.org/0000-0002-7377-8636)
- Dorothea Bankwitz (ORCID: https://orcid.org/0000-0002-8185-3202)
- Kumar Nagarathinam (ORCID: https://orcid.org/0000-0003-4200-650X)
- Tanvi Khera (ORCID: https://orcid.org/0000-0002-1287-3197)
- Edith Roth
- Oliver Dittrich‐Breiholz
- Heike Böning (ORCID: https://orcid.org/0000-0001-8969-2645)
- Hans‐Martin Jäck (ORCID: https://orcid.org/0000-0002-6332-8463)
- Barbora Veselková (ORCID: https://orcid.org/0000-0002-2065-0946)
- Johannes Cramer (ORCID: https://orcid.org/0000-0002-2595-3188)
- Jonas Obleser (ORCID: https://orcid.org/0000-0002-7619-0459)
- Sabrina S. Vollers (ORCID: https://orcid.org/0000-0002-6772-0155)
- L.J. Stroh (ORCID: https://orcid.org/0000-0002-2781-2303)
- Thomas Pietschmann (ORCID: https://orcid.org/0000-0001-6789-4422)
- Stéphane Rosset (ORCID: https://orcid.org/0000-0002-8443-6017)
- Henrike P. Ahsendorf-Abidi
Institutions
- SIB Swiss Institute of Bioinformatics (CH)
- Friedrich-Alexander-Universität Erlangen-Nürnberg (DE)
- University Medical Center Freiburg (DE)
- Medizinische Hochschule Hannover (DE)
- German Center for Infection Research (DE)
- Center for Experimental and Clinical Infection Research (DE)
- Centre for Structural Systems Biology (DE)
- École Polytechnique Fédérale de Lausanne (CH)
- University of Lübeck (DE)
Publication Details
- Journal
- Science Advances
- Published
- 2024-12-06
- DOI
- https://doi.org/10.1126/sciadv.ado2600
- Citations
- 5
- Primary Topic
- Hepatitis C virus research
- Type
- article
- Field-Weighted Citation Impact
- 1.85
Funders
- Deutsche Forschungsgemeinschaft