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Variant-specific humoral immune response to SARS-CoV-2 escape mutants arising in clinically severe, prolonged infection

Günther et al., medRxiv, doi:10.1101/2024.01.06.24300890
Jan 2024  
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Report on a prolonged SARS-CoV-2 infection in an immunocompromised patient treated with bamlanivimab, where bamlanivimab escape variant S:S494P emerged. Later, the onset of an endogenous IgM antibody response coincided with the appearance of additional escape variants carrying mutations in the NTD (S:Delta141-4) and RBD (S:E484K) of the spike protein. The triple mutant S:Delta141-4 E484K S494P became dominant until virus elimination. The study highlights the risk that immunocompromised patients treated with monoclonal antibodies like bamlanivimab can develop escape variants, especially if endogenous antibody responses are insufficient.
Efficacy is highly variant dependent. In Vitro research suggests a lack of efficacy for omicron Haars, Liu, Pochtovyi, Sheward, VanBlargan.
Günther et al., 7 Jan 2024, Germany, preprint, 15 authors. Contact:
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Variant-specific humoral immune response to SARS-CoV-2 escape mutants arising in clinically severe, prolonged infection
Theresa Günther, Michael Schöfbänker, Eva Ulla Lorentzen, Marie-Luise Romberg, Marc Tim Hennies, Rieke Neddermeyer, Marlin Maybrit Müller, Alexander Mellmann, Georg Lenz, Matthias Stelljes, Eike Roman Hrincius, Richard Vollenberg, Stephan Ludwig, Phil-Robin Tepasse, Joachim Ewald Kühn
Neutralising antibodies against the SARS-CoV-2 spike (S) protein are major determinants of protective immunity, though insufficient antibody responses may cause the emergence of escape mutants. We studied the intra-host evolution and the humoral immune response in a B-cell depleted, haemato-oncologic patient experiencing clinically severe, prolonged SARS-CoV-2 infection with a virus of lineage B.1.177.81. Bamlanivimab treatment early in infection was associated with the emergence of the bamlanivimab escape mutation S:S494P. Ten days before virus elimination, additional mutations within the N-terminal domain (NTD) and the receptor binding domain (RBD) of S were observed, of which the triple mutant S:Delta141-4 E484K S494P became dominant. Routine serology revealed no evidence of an antibody response in the patient. A detailed analysis of the variantspecific immune response by pseudotyped virus neutralisation test (pVNT), surrogate VNT (sVNT), and immunoglobulin-capture EIA showed that the onset of an IgM-dominated antibody response coincided with the appearance of escape mutations. The formation of neutralising antibodies against S:Delta141-4 E484K S494P correlated with virus elimination. One year later, the patient experienced clinically mild re-infection with Omicron BA.1.18, which was treated with sotrovimab and resulted in a massive increase of Omicron-reactive antibodies. In conclusion, the onset of an IgM-dominated endogenous immune response in an immunocompromised patient coincided with the appearance of additional mutations in the NTD and RBD of S in a bamlanivimab-resistant virus. Although virus elimination was ultimately achieved, this humoral immune response escaped detection by routine diagnosis and created a situation temporarily favouring the emergence of escape variants with known epidemiological relevance.
decision to publish. The plasmid pCG1-SARS-2-S was kindly provided by Prof. Dr. Stefan Pöhlmann (Infection Biology Unit, German Primate Centre, Göttingen, Germany). We thank Gert Zimmer (Institute of Virology and Immunology, Mittelhäusern, Switzerland) for the VSV pseudo-typed virus. We acknowledge support from the Open Access Publication Fund of the University of Muenster. All authors read and approved the final version of the manuscript and agreed to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. Contributors Declaration of interests The authors declare no conflict of interest related to this work. Parts of this study regarding the methodological establishment of the in-house sVNT and EIA were submitted in 2023 by TG to the Medical Faculty of the University of Muenster, Muenster, Germany, as their doctoral thesis entitled "Etablierung serologischer Nachweisverfahren zur Varianten-spezifischen Detektion und Differenzierung von Antikörpern gegen SARS-CoV-2". Ethics Statement The patient presented in our study has given informed consent to data collection and publication. The ethics committee of the Aerztekammer Westfalen-Lippe, Muenster, Germany, and the University of Muenster has ethically approved the study Characterisation of the Humoral Immune Response to SARS-CoV-2 in Vaccinees under the file number 2021-039-f-S. All study..
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