Spike protein genetic evolution in patients at high-risk of severe COVID-19 treated by monoclonal antibodies
et al., The Journal of Infectious Diseases, doi:10.1093/infdis/jiad523, NCT04885452, Nov 2023
18th treatment shown to reduce risk in
March 2021, now with p = 0.000095 from 34 studies, recognized in 52 countries.
Efficacy is variant dependent.
No treatment is 100% effective. Protocols
combine treatments.
6,200+ studies for
200+ treatments. c19early.org
|
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 research suggests a lack of efficacy for many omicron variants1-7.
Study covers tixagevimab/cilgavimab, casirivimab/imdevimab, and sotrovimab.
1.
Liu et al., Striking Antibody Evasion Manifested by the Omicron Variant of SARS-CoV-2, bioRxiv, doi:10.1101/2021.12.14.472719.
2.
Sheward et al., Variable loss of antibody potency against SARS-CoV-2 B.1.1.529 (Omicron), bioRxiv, doi:10.1101/2021.12.19.473354.
3.
VanBlargan et al., An infectious SARS-CoV-2 B.1.1.529 Omicron virus escapes neutralization by several therapeutic monoclonal antibodies, bioRxiv, doi:10.1101/2021.12.15.472828.
4.
Tatham et al., Lack of Ronapreve (REGN-CoV; casirivimab and imdevimab) virological efficacy against the SARS-CoV 2 Omicron variant (B.1.1.529) in K18-hACE2 mice, bioRxiv, doi:10.1101/2022.01.23.477397.
5.
Pochtovyi et al., In Vitro Efficacy of Antivirals and Monoclonal Antibodies against SARS-CoV-2 Omicron Lineages XBB.1.9.1, XBB.1.9.3, XBB.1.5, XBB.1.16, XBB.2.4, BQ.1.1.45, CH.1.1, and CL.1, Vaccines, doi:10.3390/vaccines11101533.
Leducq et al., 23 Nov 2023, prospective, France, peer-reviewed, 169 authors, study period August 2021 - December 2022, trial NCT04885452 (history).
Contact: valentin.leducq@sorbonneuniversite.fr.
Spike protein genetic evolution in patients at high-risk of severe COVID-19 treated by monoclonal antibodies
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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DOI record:
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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>",
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