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Spike protein genetic evolution in patients at high-risk of severe COVID-19 treated by monoclonal antibodies

Leducq et al., The Journal of Infectious Diseases, doi:10.1093/infdis/jiad523, NCT04885452
Nov 2023  
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Sotrovimab for COVID-19
38th treatment shown to reduce risk in May 2023
*, now known with p = 0.0017 from 22 studies, recognized in 37 countries. Efficacy is variant dependent.
Lower risk for hospitalization.
No treatment is 100% effective. Protocols combine complementary and synergistic treatments. * >10% efficacy in meta analysis with ≥3 clinical studies.
4,000+ studies for 60+ treatments.
Prospective study of 264 high-risk COVID-19 patients treated with monoclonal antibodies. Tixagevimab/cilgavimab was associated with 5 times higher risk of emergence of mutations. Treatment with sotrovimab was linked to mutations associated with higher viral loads. Mutations associated with tixagevimab/cilgavimab have been identified in multiple SARS-CoV-2 lineages, including BQ.1 and XBB. Authors conclude that using mAbs in treating high-risk COVID-19 patients could drive the genetic evolution of the virus, potentially leading to treatment resistance.
Authors recommend bi-therapies and mAbs with Fc-effector functions and emphasize the need to assess the impact of mAb treatments on the broader evolutionary trajectory of SARS-CoV-2​.
Efficacy is variant dependent. In Vitro studies predict lower efficacy for BA.1 Liu, Sheward, VanBlargan, BA.4, BA.5 Haars, XBB.1.9.3, XBB.1.5.24, XBB.2.9, CH.1.1 Pochtovyi, and no efficacy for BA.2 Zhou, ХВВ.1.9.1, XBB.1.16, BQ.1.1.45, and CL.1 Pochtovyi. US EUA has been revoked.
Study covers tixagevimab/cilgavimab, casirivimab/imdevimab, and sotrovimab.
Leducq et al., 23 Nov 2023, prospective, France, peer-reviewed, 169 authors, study period August 2021 - December 2022, trial NCT04885452 (history). Contact:
This PaperSotrovimabAll
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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