Somatic hypermutation shapes the viral escape profile of SARS-CoV-2 neutralising antibodiesResearch in context
Summary: Background: Since the onset of the COVID-19 pandemic, SARS-CoV-2 neutralising monoclonal antibodies (mAbs) are being developed for clinical use. With the appearance of new virus variants, most mAbs lost their virus-neutralising activity, highlighting the complexity of mAb development under...
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Elsevier
2025-06-01
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2352396425002142 |
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| author | Matthias Bruhn Maureen Obara Mariana Gonzalez-Hernandez Wencke Reineking Abdus Salam Monica Mirolo Imke Hinrichs AhmedElmontaser Mergani Yannic Bartsch Axel Schambach Gert Zimmer Wolfgang Baumgärtner Albert D.M.E. Osterhaus Ulrich Kalinke |
| author_facet | Matthias Bruhn Maureen Obara Mariana Gonzalez-Hernandez Wencke Reineking Abdus Salam Monica Mirolo Imke Hinrichs AhmedElmontaser Mergani Yannic Bartsch Axel Schambach Gert Zimmer Wolfgang Baumgärtner Albert D.M.E. Osterhaus Ulrich Kalinke |
| author_sort | Matthias Bruhn |
| collection | DOAJ |
| description | Summary: Background: Since the onset of the COVID-19 pandemic, SARS-CoV-2 neutralising monoclonal antibodies (mAbs) are being developed for clinical use. With the appearance of new virus variants, most mAbs lost their virus-neutralising activity, highlighting the complexity of mAb development under conditions of continuous SARS-CoV-2 evolution. Methods: Hamsters were treated with SARS-CoV-2 neutralising mAbs and then challenged with SARS-CoV-2. Recombinant VSV expressing the spike protein of SARS-CoV-2 was utilised in an in vitro system to select for antibody escape variants. Surface plasmon resonance measurements were performed to characterise the binding affinity and epitope of various mAbs. Fc-mediated effector functions of neutralising and non-neutralising mAb combinations were determined via multiple in vitro assays. Findings: Few of the mAb treated and infected hamsters experienced breakthrough infections, which derived from mutated virus that emerged in vivo. We developed an in vitro antibody escape assay that recapitulated the in vivo situation and we found that somatic hypermutations (SHM) affected the profile of viral escape hotspots that mAbs selected for. Pairwise combination of mAbs binding non-overlapping epitopes suppressed the emergence of viral mutants. The formulation with a third, non-neutralising mAb enhanced the Fc-mediated effector functions of the mAb treatment in an additive manner. Interpretation: We conclude that treatment with single mAbs rapidly leads to the formation of novel virus variants. An important function of SHM is to suppress the emergence of viral antibody escape variants. Our data suggest that the anticipatory B cell memory can be harnessed to design combinations of SARS-CoV-2 neutralising mAbs that have a reduced risk to induce viral escape. Funding: This study was supported by public funding from the German Research Foundation (DFG), the Federal Ministry of Education and Research (BMBF), the COVID-19-Research Network of the State of Lower Saxony (COFONI), the German Centre for Infection Research (DZIF), and the Helmholtz Association of German Research Centres. |
| format | Article |
| id | doaj-art-3e7d38525840461c8a445e11f27dfef6 |
| institution | OA Journals |
| issn | 2352-3964 |
| language | English |
| publishDate | 2025-06-01 |
| publisher | Elsevier |
| record_format | Article |
| series | EBioMedicine |
| spelling | doaj-art-3e7d38525840461c8a445e11f27dfef62025-08-20T01:55:33ZengElsevierEBioMedicine2352-39642025-06-0111610577010.1016/j.ebiom.2025.105770Somatic hypermutation shapes the viral escape profile of SARS-CoV-2 neutralising antibodiesResearch in contextMatthias Bruhn0Maureen Obara1Mariana Gonzalez-Hernandez2Wencke Reineking3Abdus Salam4Monica Mirolo5Imke Hinrichs6AhmedElmontaser Mergani7Yannic Bartsch8Axel Schambach9Gert Zimmer10Wolfgang Baumgärtner11Albert D.M.E. Osterhaus12Ulrich Kalinke13Institute for Experimental Infection Research, TWINCORE, Centre for Experimental and Clinical Infection Research, a joint venture between the Helmholtz Centre for Infection Research and the Hannover Medical School, Hannover, GermanyInstitute for Experimental Infection Research, TWINCORE, Centre for Experimental and Clinical Infection Research, a joint venture between the Helmholtz Centre for Infection Research and the Hannover Medical School, Hannover, GermanyResearch Center for Emerging Infections and Zoonoses, University of Veterinary Medicine Hannover, Foundation, Hannover, GermanyDepartment of Pathology, University of Veterinary Medicine Hannover, Hannover, GermanyInstitute for Experimental Infection Research, TWINCORE, Centre for Experimental and Clinical Infection Research, a joint venture between the Helmholtz Centre for Infection Research and the Hannover Medical School, Hannover, GermanyResearch Center for Emerging Infections and Zoonoses, University of Veterinary Medicine Hannover, Foundation, Hannover, GermanyJunior Research Group Anti-viral Antibody-Omics, TWINCORE, Centre for Experimental and Clinical Infection Research, a joint venture between the Helmholtz Centre for Infection Research and the Hannover Medical School, Hannover, GermanyResearch Center for Emerging Infections and Zoonoses, University of Veterinary Medicine Hannover, Foundation, Hannover, Germany; Department of Biochemistry, University of Veterinary Medicine Hannover, Hannover, GermanyJunior Research Group Anti-viral Antibody-Omics, TWINCORE, Centre for Experimental and Clinical Infection Research, a joint venture between the Helmholtz Centre for Infection Research and the Hannover Medical School, Hannover, GermanyInstitute of Experimental Hematology, Hannover Medical School, Hannover, Germany; Division of Hematology/Oncology, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA; German Center for Infection Research (DZIF), Partner Site Hannover–Braunschweig, Hannover, GermanyInstitute of Virology and Immunology (IVI), Mittelhäusern and Bern, Bern, Switzerland; Department of Infectious Diseases and Pathobiology, Vetsuisse Faculty, University of Bern, Bern, SwitzerlandDepartment of Pathology, University of Veterinary Medicine Hannover, Hannover, GermanyResearch Center for Emerging Infections and Zoonoses, University of Veterinary Medicine Hannover, Foundation, Hannover, GermanyInstitute for Experimental Infection Research, TWINCORE, Centre for Experimental and Clinical Infection Research, a joint venture between the Helmholtz Centre for Infection Research and the Hannover Medical School, Hannover, Germany; German Center for Infection Research (DZIF), Partner Site Hannover–Braunschweig, Hannover, Germany; Cluster of Excellence RESIST (EXC 2155), Hannover Medical School, Hannover, Germany; Corresponding author. Institute for Experimental Infection Research, TWINCORE, Centre for Experimental and Clinical Infection Research, a joint venture between the Helmholtz Centre for Infection Research and the Hannover Medical School, Hannover, Germany.Summary: Background: Since the onset of the COVID-19 pandemic, SARS-CoV-2 neutralising monoclonal antibodies (mAbs) are being developed for clinical use. With the appearance of new virus variants, most mAbs lost their virus-neutralising activity, highlighting the complexity of mAb development under conditions of continuous SARS-CoV-2 evolution. Methods: Hamsters were treated with SARS-CoV-2 neutralising mAbs and then challenged with SARS-CoV-2. Recombinant VSV expressing the spike protein of SARS-CoV-2 was utilised in an in vitro system to select for antibody escape variants. Surface plasmon resonance measurements were performed to characterise the binding affinity and epitope of various mAbs. Fc-mediated effector functions of neutralising and non-neutralising mAb combinations were determined via multiple in vitro assays. Findings: Few of the mAb treated and infected hamsters experienced breakthrough infections, which derived from mutated virus that emerged in vivo. We developed an in vitro antibody escape assay that recapitulated the in vivo situation and we found that somatic hypermutations (SHM) affected the profile of viral escape hotspots that mAbs selected for. Pairwise combination of mAbs binding non-overlapping epitopes suppressed the emergence of viral mutants. The formulation with a third, non-neutralising mAb enhanced the Fc-mediated effector functions of the mAb treatment in an additive manner. Interpretation: We conclude that treatment with single mAbs rapidly leads to the formation of novel virus variants. An important function of SHM is to suppress the emergence of viral antibody escape variants. Our data suggest that the anticipatory B cell memory can be harnessed to design combinations of SARS-CoV-2 neutralising mAbs that have a reduced risk to induce viral escape. Funding: This study was supported by public funding from the German Research Foundation (DFG), the Federal Ministry of Education and Research (BMBF), the COVID-19-Research Network of the State of Lower Saxony (COFONI), the German Centre for Infection Research (DZIF), and the Helmholtz Association of German Research Centres.http://www.sciencedirect.com/science/article/pii/S2352396425002142Viral escapeSARS-CoV-2Monoclonal antibodiesSomatic hypermutationBinding affinity |
| spellingShingle | Matthias Bruhn Maureen Obara Mariana Gonzalez-Hernandez Wencke Reineking Abdus Salam Monica Mirolo Imke Hinrichs AhmedElmontaser Mergani Yannic Bartsch Axel Schambach Gert Zimmer Wolfgang Baumgärtner Albert D.M.E. Osterhaus Ulrich Kalinke Somatic hypermutation shapes the viral escape profile of SARS-CoV-2 neutralising antibodiesResearch in context EBioMedicine Viral escape SARS-CoV-2 Monoclonal antibodies Somatic hypermutation Binding affinity |
| title | Somatic hypermutation shapes the viral escape profile of SARS-CoV-2 neutralising antibodiesResearch in context |
| title_full | Somatic hypermutation shapes the viral escape profile of SARS-CoV-2 neutralising antibodiesResearch in context |
| title_fullStr | Somatic hypermutation shapes the viral escape profile of SARS-CoV-2 neutralising antibodiesResearch in context |
| title_full_unstemmed | Somatic hypermutation shapes the viral escape profile of SARS-CoV-2 neutralising antibodiesResearch in context |
| title_short | Somatic hypermutation shapes the viral escape profile of SARS-CoV-2 neutralising antibodiesResearch in context |
| title_sort | somatic hypermutation shapes the viral escape profile of sars cov 2 neutralising antibodiesresearch in context |
| topic | Viral escape SARS-CoV-2 Monoclonal antibodies Somatic hypermutation Binding affinity |
| url | http://www.sciencedirect.com/science/article/pii/S2352396425002142 |
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