Total escape of SARS-CoV-2 from dual monoclonal antibody therapy in an immunocompromised patient

Lena Jaki, Sebastian Weigang, Lisa Kern, Stefanie Kramme, Antoni G. Wrobel, Andrea B. Grawitz, Philipp Nawrath, Stephen R. Martin, Theo Dähne, Julius Beer, Miriam Disch, Philipp Kolb, Lisa Gutbrod, Sandra Reuter, Klaus Warnatz, Martin Schwemmle, Steven J. Gamblin, Elke Neumann-Haefelin, Daniel Schnepf, Thomas Welte, Georg Kochs, Daniela Huzly, Marcus Panning () and Jonas Fuchs ()
Additional contact information
Lena Jaki: Freiburg University Medical Center, Faculty of Medicine, University of Freiburg
Sebastian Weigang: Freiburg University Medical Center, Faculty of Medicine, University of Freiburg
Lisa Kern: Freiburg University Medical Center, Faculty of Medicine, University of Freiburg
Stefanie Kramme: Freiburg University Medical Center, University of Freiburg
Antoni G. Wrobel: The Francis Crick Institute
Andrea B. Grawitz: Freiburg University Medical Center, Faculty of Medicine, University of Freiburg
Philipp Nawrath: The Francis Crick Institute
Stephen R. Martin: The Francis Crick Institute
Theo Dähne: Freiburg University Medical Center, Faculty of Medicine, University of Freiburg
Julius Beer: Freiburg University Medical Center, Faculty of Medicine, University of Freiburg
Miriam Disch: Freiburg University Medical Center, Faculty of Medicine, University of Freiburg
Philipp Kolb: Freiburg University Medical Center, Faculty of Medicine, University of Freiburg
Lisa Gutbrod: Freiburg University Medical Center, Faculty of Medicine, University of Freiburg
Sandra Reuter: Freiburg University Medical Center, University of Freiburg
Klaus Warnatz: Freiburg University Medical Center, Faculty of Medicine, University of Freiburg
Martin Schwemmle: Freiburg University Medical Center, Faculty of Medicine, University of Freiburg
Steven J. Gamblin: The Francis Crick Institute
Elke Neumann-Haefelin: Freiburg University Medical Center, Faculty of Medicine, University of Freiburg
Daniel Schnepf: Freiburg University Medical Center, Faculty of Medicine, University of Freiburg
Thomas Welte: Freiburg University Medical Center, Faculty of Medicine, University of Freiburg
Georg Kochs: Freiburg University Medical Center, Faculty of Medicine, University of Freiburg
Daniela Huzly: Freiburg University Medical Center, Faculty of Medicine, University of Freiburg
Marcus Panning: Freiburg University Medical Center, Faculty of Medicine, University of Freiburg
Jonas Fuchs: Freiburg University Medical Center, Faculty of Medicine, University of Freiburg

Nature Communications, 2023, vol. 14, issue 1, 1-14

Abstract: Abstract Monoclonal antibodies (mAbs) directed against the spike of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are effective therapeutic options to combat infections in high-risk patients. Here, we report the adaptation of SARS-CoV-2 to the mAb cocktail REGN-COV in a kidney transplant patient with hypogammaglobulinemia. Following mAb treatment, the patient did not clear the infection. During viral persistence, SARS-CoV-2 acquired three novel spike mutations. Neutralization and mouse protection analyses demonstrate a complete viral escape from REGN-COV at the expense of ACE-2 binding. Final clearance of the virus occurred upon reduction of the immunosuppressive regimen and total IgG substitution. Serology suggests that the development of highly neutralizing IgM rather than IgG substitution aids clearance. Our findings emphasise that selection pressure by mAbs on SARS-CoV-2 can lead to development of escape variants in immunocompromised patients. Thus, modification of immunosuppressive therapy, if possible, might be preferable to control and clearance of the viral infection.

Date: 2023
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DOI: 10.1038/s41467-023-37591-w

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