Spike protein genetic evolution in patients at high-risk of severe COVID-19 treated by monoclonal antibodies
Valentin Leducq, Karen Zafilaza, Antoine Fauchois, Emna Ghidaoui, Sophie Sayon, Céline Dorival, Marie-Laure Meledje, Clovis Lusivika-Nzinga, Youri Yordanov, Guillaume Martin-Blondel, Fabrice Carrat, Anne-Geneviève Marcelin, Cathia Soulie, Magali Garcia, Valentin Giraud, Agathe Metais, France Cazenave-Roblot, Jean-Philippe Martellosio, Anne-Marie Ronchetti, Thomas Gabas, Naima Had- Jadj, Célia Salanoubat, Amélie Chabrol, Pierre Housset, Agathe Par- Don, Anne-Laure Faucon, Valérie Caudwell, Latifa Hanafi, Laurent Alric, Grégory Pugnet, Mor- Gane Mourguet, Eva Bories, Delphine Bonnet, Sandrine Charpentier, Pierre Delobel, Alexa Debard, Colleen Beck, Xavier Boumaza, Stella Rousset, Fanny Lanternier, Claire Delage, Elisabete Gomes Pires, Morgane Cheminant, Nathalie Chavarot, Anthony Chauvin, Xavier Eyer, Véronique Delcey, Simon Bessis, Romain Gueneau, Pelagie Thibaut, Marine Nadal, Mar- Tin Siguier, Marwa Bachir, Christia Palacios, Valérie Pourcher, Antoine Faycal, Vincent Berot, Cécile Brin, Siham Djebara, Karen Zafilaza, Stephane Marot, Sophie Sayon, Valentin Leducq, Karine Lacombe, Yasmine Abi Aad, Thibault Chiarabini, Raynald Feliho, Nadia Valin, Fabien Brigant, Julien Boize, Pierre-Clément Thiébaud, Marie Moreau, Charlotte Billard, Nathalie De Castro, Geoffroy Liégeon, Blandine Denis, Jean-Michel Molina, Lucia Etheve, André Cabié, Sylvie Abel, Ornella Cabras, Karine Guitteaud, Sandrine Pierre-François, Vincent Dubee, Diama Ndiaye, Jonathan Pehlivan, Michael Phelippeau, Rafael Mahieu, Charles Cazanave, Alexandre Duvignaud, Thierry Pistone, Arnaud Desclaux, Didier Neau, Jean-François Faucher, Benjamin Festou, Magali Dupuy-Grasset, Véronique Loustaud-Ratti, Delphine Chainier, Nathan Peiffer-Smadja, Olivia Da Conceicao, Michael Thy, Lio Collas, Cindy Godard, Donia Bouzid, Vittiaroat Ing, Laurent Pereira, Thomas Pavlowsky, Camille Ravaut, Antoine Asquier-Khati, David Boutoille, Marie Chauveau, Colin Deschanvres, François Raffi, Audrey Le Bot, Marine Cailleaux, François Benezit, Anne Maillard, Benoit Hue, Pierre Tattevin, François Coustilleres, Claudia Carvalho- Schneider, Simon Jamard, Laetitia Petit, Karl Stefic, Natacha Mrozek, Clement Theis, Magali Vidal, Leo Sauvat, Delphine Martineau, Benjamin Lefèvre, Guillaume Baronnet, Agnès Didier, Florence Ader, Thomas Perpoint, Anne Conrad, Paul Chabert, Pierre Chauvelot, Aurélie Martin, Paul Loubet, Julien Mazet, Romaric Larcher, Didier Laureillard, Mathilde De- Vaux, Jérôme Frey, Amos Woerlen, Aline Remillon, Laure Absensur-Vuillaume, Pauline Bouquet, Albert Trinh-Duc, Patrick Rispal, Philippe Petua, Julien Carillo, Aurore Perrot, Karen Delavigne, Pierre Cougoul, Jérémie Dion, Odile Rauzy, Yazdan Yazdanpanah, Ventzislava Petrov-Sanchez, Alpha Diallo, Soizic Le Mestre, Guillaume Le Meut, Isabelle Goderel, Frédéric Chau, Brahim Soltana, Jessica Chane Tang, Jeremie Guedj, Yvanie Caille
The Journal of Infectious Diseases, doi:10.1093/infdis/jiad523
Background High-risk patients, often immunocompromised and not responding to vaccine, continue to experience severe COVID-19 and death. Monoclonal antibodies (mAbs) were shown effective to prevent severe COVID-19 for these patients. Nevertheless, concerns about the emergence of resistance mutations were raised.
Methods We conducted a multicentric prospective cohort study, including 264 patients with mildto moderate COVID-19 at high risk for progression to severe COVID-19 and treated early with Casirivimab/Imdevimab, Sotrovimab or Tixagevimab/Cilgavimab. We sequenced the SARS-CoV-2 genome during follow-up and searched for emerging Spike mutations.
DOI: 10.1093/infdis/jiad523 9 Together, these data suggest that mAb monotherapy, without Fc-effector functions, is highly sensitive to the emergence of mutations located in the targeted epitope reducing neutralizing activity and may explain the higher risk of mutation emergence with Tixagevimab/Cilgavimab. In conclusion, our analysis highlights how using mAbs to treat high-risk COVID-19 patients can drive genetic evolution of SARS-CoV-2, potentially leading to treatment resistance through the rapid and frequent acquisition of mutations in Spike protein in immunocompromised patients. To mitigate this risk, our findings suggest that employing bi-therapies and mAbs featuring Fc-effector functions may be beneficial. Moreover, we have identified these resistance mutations across multiple SARS-CoV-2 lineages, including various VOCs, emphasizing the need to assess the impact of mAb treatments on SARS-CoV-2 evolution more broadly within the population.
Author contributions
Conceptualization
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'abstract': '<jats:title>Abstract</jats:title>\n'
' <jats:sec>\n'
' <jats:title>Background</jats:title>\n'
' <jats:p>High-risk patients, often immunocompromised and not responding to '
'vaccine, continue to experience severe COVID-19 and death. Monoclonal antibodies (mAbs) were '
'shown effective to prevent severe COVID-19 for these patients. Nevertheless, concerns about '
'the emergence of resistance mutations were raised.</jats:p>\n'
' </jats:sec>\n'
' <jats:sec>\n'
' <jats:title>Methods</jats:title>\n'
' <jats:p>We conducted a multicentric prospective cohort study, including 264 '
'patients with mild-to moderate COVID-19 at high risk for progression to severe COVID-19 and '
'treated early with Casirivimab/Imdevimab, Sotrovimab or Tixagevimab/Cilgavimab. We sequenced '
'the SARS-CoV-2 genome during follow-up and searched for emerging Spike mutations.</jats:p>\n'
' </jats:sec>\n'
' <jats:sec>\n'
' <jats:title>Results</jats:title>\n'
' <jats:p>Immunocompromised patients have a 6-fold increased risk of '
'developing mutations, which are associated with a prolonged duration of viral clearance but '
'no clinical worsening. Emerging P337S/R/L/H, E340D/K/A/Q/V/G and K356T/R substitutions in '
'patients treated with Sotrovimab are associated with higher viral RNA loads for up to 14 days '
'post-treatment initiation. Tixagevimab/Cilgavimab is associated with a 5-fold increased risk '
'of developing mutations. R346K/I/T/S and K444R/N/M substitutions associated with '
'Tixagevimab/Cilgavimab have been identified in multiple SARS-CoV-2 lineages, including BQ.1 '
'and XBB.</jats:p>\n'
' </jats:sec>\n'
' <jats:sec>\n'
' <jats:title>Conclusions</jats:title>\n'
' <jats:p>In conclusion, the probability of emerging mutations arising in '
'response to mAbs is significant, emphasizing the crucial need to investigate these mutations '
'thoroughly and assess their impact on patients and the evolutionary trajectory of the '
'SARS-CoV-2.</jats:p>\n'
' </jats:sec>',
'DOI': '10.1093/infdis/jiad523',
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'date-time': '2023-11-21T16:45:08Z',
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'title': 'Spike protein genetic evolution in patients at high-risk of severe COVID-19 treated by '
'monoclonal antibodies',
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{'given': 'Mathilde', 'family': 'De- vaux', 'sequence': 'additional', 'affiliation': []},
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'member': '286',
'published-online': {'date-parts': [[2023, 11, 23]]},
'container-title': 'The Journal of Infectious Diseases',
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'date-time': '2023-11-23T20:55:15Z',
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'URL': 'http://dx.doi.org/10.1093/infdis/jiad523',
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'ISSN': ['0022-1899', '1537-6613'],
'subject': ['Infectious Diseases', 'Immunology and Allergy'],
'published': {'date-parts': [[2023, 11, 23]]}}
