Characterisation of the antibody-mediated selective pressure driving intra-host evolution of SARS-CoV-2 in prolonged infection.
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 humoral immune response causing intra-host evolution in a B-cell depleted, haemato-oncologi...
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| Format: | Article |
| Language: | English |
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Public Library of Science (PLoS)
2024-10-01
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| Series: | PLoS Pathogens |
| Online Access: | https://doi.org/10.1371/journal.ppat.1012624 |
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| author | Michael Schoefbaenker Theresa Günther Eva Ulla Lorentzen Marie-Luise Romberg Marc Tim Hennies Rieke Neddermeyer Marlin Maybrit Müller Alexander Mellmann Chiara Robin Bojarzyn Georg Lenz Matthias Stelljes Eike Roman Hrincius Richard Vollenberg Stephan Ludwig Phil-Robin Tepasse Joachim Ewald Kühn |
| author_facet | Michael Schoefbaenker Theresa Günther Eva Ulla Lorentzen Marie-Luise Romberg Marc Tim Hennies Rieke Neddermeyer Marlin Maybrit Müller Alexander Mellmann Chiara Robin Bojarzyn Georg Lenz Matthias Stelljes Eike Roman Hrincius Richard Vollenberg Stephan Ludwig Phil-Robin Tepasse Joachim Ewald Kühn |
| author_sort | Michael Schoefbaenker |
| collection | DOAJ |
| description | 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 humoral immune response causing intra-host evolution 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. Following bamlanivimab treatment at an early stage of infection, the patient developed a bamlanivimab-resistant mutation, S:S494P. After five weeks of apparent genetic stability, the emergence of additional substitutions and deletions within the N-terminal domain (NTD) and the receptor binding domain (RBD) of S was observed. Notably, the composition and frequency of escape mutations changed in a short period with an unprecedented dynamic. The triple mutant S:Delta141-4 E484K S494P became dominant until virus elimination. Routine serology revealed no evidence of an antibody response in the patient. A detailed analysis of the variant-specific immune response by pseudotyped virus neutralisation test, surrogate virus neutralisation test, and immunoglobulin-capture enzyme immunoassay 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 an increase in 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 rapid emergence of various antibody escape mutants with known epidemiological relevance. |
| format | Article |
| id | doaj-art-ebe092f1c6914f7e860e517dc2c22ecb |
| institution | Kabale University |
| issn | 1553-7366 1553-7374 |
| language | English |
| publishDate | 2024-10-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS Pathogens |
| spelling | doaj-art-ebe092f1c6914f7e860e517dc2c22ecb2025-01-22T05:30:52ZengPublic Library of Science (PLoS)PLoS Pathogens1553-73661553-73742024-10-012010e101262410.1371/journal.ppat.1012624Characterisation of the antibody-mediated selective pressure driving intra-host evolution of SARS-CoV-2 in prolonged infection.Michael SchoefbaenkerTheresa GüntherEva Ulla LorentzenMarie-Luise RombergMarc Tim HenniesRieke NeddermeyerMarlin Maybrit MüllerAlexander MellmannChiara Robin BojarzynGeorg LenzMatthias StelljesEike Roman HrinciusRichard VollenbergStephan LudwigPhil-Robin TepasseJoachim Ewald KühnNeutralising 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 humoral immune response causing intra-host evolution 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. Following bamlanivimab treatment at an early stage of infection, the patient developed a bamlanivimab-resistant mutation, S:S494P. After five weeks of apparent genetic stability, the emergence of additional substitutions and deletions within the N-terminal domain (NTD) and the receptor binding domain (RBD) of S was observed. Notably, the composition and frequency of escape mutations changed in a short period with an unprecedented dynamic. The triple mutant S:Delta141-4 E484K S494P became dominant until virus elimination. Routine serology revealed no evidence of an antibody response in the patient. A detailed analysis of the variant-specific immune response by pseudotyped virus neutralisation test, surrogate virus neutralisation test, and immunoglobulin-capture enzyme immunoassay 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 an increase in 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 rapid emergence of various antibody escape mutants with known epidemiological relevance.https://doi.org/10.1371/journal.ppat.1012624 |
| spellingShingle | Michael Schoefbaenker Theresa Günther Eva Ulla Lorentzen Marie-Luise Romberg Marc Tim Hennies Rieke Neddermeyer Marlin Maybrit Müller Alexander Mellmann Chiara Robin Bojarzyn Georg Lenz Matthias Stelljes Eike Roman Hrincius Richard Vollenberg Stephan Ludwig Phil-Robin Tepasse Joachim Ewald Kühn Characterisation of the antibody-mediated selective pressure driving intra-host evolution of SARS-CoV-2 in prolonged infection. PLoS Pathogens |
| title | Characterisation of the antibody-mediated selective pressure driving intra-host evolution of SARS-CoV-2 in prolonged infection. |
| title_full | Characterisation of the antibody-mediated selective pressure driving intra-host evolution of SARS-CoV-2 in prolonged infection. |
| title_fullStr | Characterisation of the antibody-mediated selective pressure driving intra-host evolution of SARS-CoV-2 in prolonged infection. |
| title_full_unstemmed | Characterisation of the antibody-mediated selective pressure driving intra-host evolution of SARS-CoV-2 in prolonged infection. |
| title_short | Characterisation of the antibody-mediated selective pressure driving intra-host evolution of SARS-CoV-2 in prolonged infection. |
| title_sort | characterisation of the antibody mediated selective pressure driving intra host evolution of sars cov 2 in prolonged infection |
| url | https://doi.org/10.1371/journal.ppat.1012624 |
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