To the Editor,
In their recent article, Yang et al. 1 reported reduced COVID-19 severity after sotrovimab infusion in solid-organ-transplant (SOT) recipients with SARS-CoV-2 infection. Since the emergence of the BA.2 omicron subvariant, this monoclonal antibody (mAb) therapy is no longer used in France due to its low neutralizing activity against BA.2 and its capacity to induce resistance-associated spike mutations 2 , 3. A new combination of two mAbs, tixagevimab-cilgavimab, has recently been authorized in France as an emergency treatment of SARS-CoV-2 BA.2 infections in patients at risk of severe COVID-19. While this association has been shown to protect against severe COVID-19 infections 4, little is known of its capacity to provoke spike mutations in the virus due to selective pressure.
We collected nasopharyngeal (NP) samples from 18 ambulatory patients who were given a single intravenous infusion of tixagevimab-cilgavimab (300 mg/300 mg) between March and May 2022 at the Toulouse-University-Hospital, France. NP samples were taken from them before (day 0) and 7 and 14 days after treatment (Supplementary Appendix).
These patients (median age: 63 years; 67% men), included 14 (78%) who were immunocompromised (11 SOT recipients), 3 with pulmonary disease and one who was obese with high blood pressure. All were infected with the omicron BA.2 subvariant. None of these patients required hospitalization. The median SARS-CoV-2 NP virus load decreased from 5.8 (interquartile range (IQR), 5.3–6.5) log10 copies/ml before infusion to 4.5 (IQR, 3.8–5.7) log10 copies/ml 7 days post-infusion (p = 0.04). The virus loads of 11 patients were high enough for sequencing analysis before and after infusion 5. Resistance-associated mutations in the spike protein, positions 444, 346 and 452 were detected in 8/11 (73%) patients, 7 to 14 days post-infusion (Table 1 ). When the mutation was detected, the NP virus load increased in 3 patients, slowly decreased (<1 log10 copies/ml) in 4 patients, and significantly declined (>1 log10 copies/ml) in only 2 patients.
Table 1.
Clinical characteristics and SARS-CoV-2 evolution of tixagevimab-cilgavimab-treated patients developing resistance-associated mutation.
| Patient number | Clinical characteristics | SARS-CoV-2 vaccination status a | Days after tixagevimab-cilgavimab infusion b | Resistance mutation acquired (% in quasispecies) | Number of haplotypes | Nasopharyngeal virus load |
|---|---|---|---|---|---|---|
| #1 | Kidney transplantation | boosted | 7 | K444R (26%) | 6 | rebound |
| #2 | Pancreas and kidney transplantation | boosted | 14 | K444R (64%) K444N (30%) | 2 | rebound |
| #3 | Kidney transplantation | boosted | 14 | K444N (100%) | 1 | rebound |
| #4 | Lung transplantation | boosted | 7 | K444R (88%) | 5 | <1 log10 decline |
| #5 | Primary immunodeficiency | boosted | 7 | R346T (5%) K444N (17%) | 10 | <1 log10 decline |
| #6 | Carboplatin-Taxol treatment | boosted | 14 | R346T (25%) K444N (40%) | 10 | <1 log10 decline |
| #7 | Liver transplantation | boosted | 14 | L452M (8%) | 4 | <1 log10 decline |
| #8 | Heart transplantation | boosted | 7 | K444R (98%) | 2 | ≥1 log10 decline |
| #9 | Rituximab treatment | boosted | 7 | K444N (18%) K444R (22%) | 8 | ≥1 log10 decline |
Vaccination with SARS-CoV-2 mRNA-based vaccine (boosted: 3 doses of mRNA-based vaccine).
Time after tixagevimab-cilgavimab infusion when the mutation was detected.
The decrease of virus load (1.3 log10 copies /ml) observed 7 days after tixagevimab-cilgavimab infusion was smaller than that of a group of 10 untreated immunocompromised SARS-CoV-2 alpha-infected patients (2.5 log10 copies/ml) 5. This poor response could be due to the omicron lineage mutations S477N and Q493R in the receptor-binding domain of the spike protein, as they are responsible for tixagevimab having no neutralizing activity 6. Our results highlight the high risk of developing spike-protein mutations that confer resistance to cilgavimab of patients previously given tixagevimab-cilgavimab, as occurred in patients treated with sotrovimab alone 3. Patients infected with BA.2 or the new omicron subvariants BA.4/5, against which the neutralizing activity of cilgavimab is lower than that against BA.2 7 , 8, require close virological monitoring to minimize the risk of transmission of resistant variants in the community. New neutralizing mAbs should be designed to improve anti-SARS-CoV-2 activity and limit the development of mutations that confer resistance.
Declaration of Competing Interest
The authors declare no conflict of interest.
Acknowledgments
Funding
The Toulouse Institute for Infectious and Inflammatory Diseases (Infinity) - INSERM UMR1291 - CNRS UMR5051 - Toulouse III University, and the ANRS-MIE (Emergen, Quasicov study) provided financial support.
Acknowledgment
The English text was edited by Dr Owen Parkes.
Footnotes
Supplementary material associated with this article can be found, in the online version, at doi:10.1016/j.jinf.2022.07.014.
Appendix. Supplementary materials
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