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Resistance mutations in SARS-CoV-2 omicron variant after tixagevimab-cilgavimab treatment

  • Camille Vellas
    Correspondence
    Corresponding author at: IFB, Laboratoire de Virologie, 330 av de Grande Bretagne, 31052 Toulouse, France.
    Affiliations
    INSERM UMR1291 - CNRS UMR5051 - Université Toulouse III, Toulouse Institute for Infectious and Inflammatory Diseases (Infinity), Toulouse F-31300, France

    Toulouse University Hospital, Virology Laboratory, Toulouse F-31300, France

    Université Toulouse III Paul Sabatier, Toulouse F-31300, France
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  • Nassim Kamar
    Affiliations
    INSERM UMR1291 - CNRS UMR5051 - Université Toulouse III, Toulouse Institute for Infectious and Inflammatory Diseases (Infinity), Toulouse F-31300, France

    Université Toulouse III Paul Sabatier, Toulouse F-31300, France

    Toulouse University Hospital, Department of Nephrology, Dialysis, and Multi-Organ Transplantation, Toulouse, F-31300 France
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  • Jacques Izopet
    Correspondence
    Alternate corresponding author: IFB, Laboratoire de Virologie, 330 av de Grande Bretagne, 31052 Toulouse, France.
    Affiliations
    INSERM UMR1291 - CNRS UMR5051 - Université Toulouse III, Toulouse Institute for Infectious and Inflammatory Diseases (Infinity), Toulouse F-31300, France

    Toulouse University Hospital, Virology Laboratory, Toulouse F-31300, France

    Université Toulouse III Paul Sabatier, Toulouse F-31300, France
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      Keywords

      To the Editor,
      In their recent article, Yang et al.
      • Yang M.
      • Li A.
      • Wang Y.
      • Tran C.
      • Zhao S.
      • Ao G.
      Monoclonal antibody therapy improves severity and mortality of COVID-19 in organ transplant recipients: a meta-analysis.
      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
      • Takashita E.
      • Kinoshita N.
      • Yamayoshi S.
      • Sakai-Tagawa Y.
      • Fujisaki S.
      • Ito M.
      • et al.
      Efficacy of Antibodies and Antiviral Drugs against Covid-19 Omicron Variant.
      ,
      • Vellas C.
      • Trémeaux P.
      • Del Bello A.
      • Latour J.
      • Jeanne N.
      • Ranger N.
      • et al.
      Resistance mutations in SARS-CoV-2 omicron variant in patients treated with sotrovimab.
      . 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
      • Montgomery H.
      • Hobbs F.D.R.
      • Padilla F.
      • Arbetter D.
      • Templeton A.
      • Seegobin S.
      • et al.
      Efficacy and safety of intramuscular administration of tixagevimab-cilgavimab for early outpatient treatment of COVID-19 (TACKLE): a phase 3, randomised, double-blind, placebo-controlled trial.
      , 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
      • Vellas C.
      • Del Bello A.
      • Debard A.
      • Steinmeyer Z.
      • Tribaudeau L.
      • Ranger N.
      • et al.
      Influence of treatment with neutralizing monoclonal antibodies on the SARS-CoV-2 nasopharyngeal load and quasispecies.
      . 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 1Clinical characteristics and SARS-CoV-2 evolution of tixagevimab-cilgavimab-treated patients developing resistance-associated mutation.
      Patient numberClinical characteristicsSARS-CoV-2 vaccination status
      Vaccination with SARS-CoV-2 mRNA-based vaccine (boosted: 3 doses of mRNA-based vaccine).
      Days after tixagevimab-cilgavimab infusion
      Time after tixagevimab-cilgavimab infusion when the mutation was detected.
      Resistance mutation acquired (% in quasispecies)Number of haplotypesNasopharyngeal virus load
      #1Kidney transplantationboosted7K444R (26%)6rebound
      #2Pancreas and kidney transplantationboosted14K444R (64%) K444N (30%)2rebound
      #3Kidney transplantationboosted14K444N (100%)1rebound
      #4Lung transplantationboosted7K444R (88%)5<1 log10 decline
      #5Primary immunodeficiencyboosted7R346T (5%) K444N (17%)10<1 log10 decline
      #6Carboplatin-Taxol treatmentboosted14R346T (25%) K444N (40%)10<1 log10 decline
      #7Liver transplantationboosted14L452M (8%)4<1 log10 decline
      #8Heart transplantationboosted7K444R (98%)2≥1 log10 decline
      #9Rituximab treatmentboosted7K444N (18%) K444R (22%)8≥1 log10 decline
      a Vaccination with SARS-CoV-2 mRNA-based vaccine (boosted: 3 doses of mRNA-based vaccine).
      b 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)
      • Vellas C.
      • Del Bello A.
      • Debard A.
      • Steinmeyer Z.
      • Tribaudeau L.
      • Ranger N.
      • et al.
      Influence of treatment with neutralizing monoclonal antibodies on the SARS-CoV-2 nasopharyngeal load and quasispecies.
      . 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
      • Dejnirattisai W.
      • Huo J.
      • Zhou D.
      • Zahradn.ík J.
      • Supasa P.
      • Liu C.
      • et al.
      SARS-CoV-2 Omicron-B.1.1.529 leads to widespread escape from neutralizing antibody responses.
      . 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
      • Vellas C.
      • Trémeaux P.
      • Del Bello A.
      • Latour J.
      • Jeanne N.
      • Ranger N.
      • et al.
      Resistance mutations in SARS-CoV-2 omicron variant in patients treated with sotrovimab.
      . 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
      • Yamasoba D.
      • Kosugi Y.
      • Kimura I.
      • Fujita S.
      • Uriu K.
      • Ito J.
      • et al.
      Neutralisation sensitivity of SARS-CoV-2 omicron subvariants to therapeutic monoclonal antibodies.
      ,
      • Tuekprakhon A.
      • Huo J.
      • Nutalai R.
      • Dijokaite-Guraliuc A.
      • Zhou D.
      • Ginn Helen M.
      • et al.
      Antibody escape of SARS-CoV-2 Omicron BA.4 and BA.5 from vaccine and BA.1 serum.
      , 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.

      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.

      Appendix. Supplementary materials

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