Resistance Mutations in SARS-CoV-2 Delta Variant after Sotrovimab Use

Rockett, Rebecca; Basile, Kerri; Maddocks, Susan; Fong, Winkie; Agius, Jessica E; Johnson-Mackinnon, Jessica; Arnott, Alicia; Chandra, Shona; Gall, Mailie; Draper, Jenny; Martínez, Elena; E, Sim; Lee, Clement; Ngo, Christine Ngoc; Ramsperger, Marc; Ginn, Andrew N.; Wang, Qinning; Fennell, Michael; Ko, Danny; Lim, Heeji; Gilroy, Nicky; O’Sullivan, Matthew V. N.; Chen, Sharon C‐A; Kok, Jen; Dwyer, Dominic E.; Sintchenko, Vitali

doi:10.1056/nejmc2120219

Cited by 163 publications

(153 citation statements)

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“…Indications include patients with respiratory, cardiac, metabolic, and immunosuppression comorbidities. Rockett and colleagues have recently shown that among 100 patients infected by Delta variant and treated with sotrovimab monotherapy, 4 were immunocompromised and rapidly developed resistant mutations in the spike at positions 337 and/or 340 (S:337 and/or S:340) 1,2 . As sotrovimab is one of the few monoclonal antibodies that retains efficacy against the widely circulating BA.1 sublineage (Omicron variant), monitoring the prevalence of these mutations is crucial 3 .…”

Section: Manuscriptmentioning

confidence: 99%

Sotrovimab drives SARS-CoV-2 Omicron variant evolution in immunocompromised patients

Destras

Bal

Simon

et al. 2022

Preprint

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After monoclonal antibody sotrovimab implementation, Rockett et al have warned on March 9th about two resistant mutations in the spike at position 337 and 340 occurring within the first week in four immunocompromised patients infected by a Delta variant and resulting in viable infection up to 25 days. As sotrovimab is currently the only effective treatment against BA.1 lineage of Omicron variant, we investigated the presence of these mutations in our 22,908 Omicron sequences performed from December 2021 to March 2022. Among 25 Omicron sequences with S:337 and S:340 substitutions, 9 were reported in six patients who had available clinical data and a follow up. All were immunicompromised, and presented a rapid selection of these mutations after sotrovimab monotherapy infusion. With these findings, we underscore that although these mutations are rare, they have been exclusively reported in immunocompromised patients treated with sotrovimab. We urge to consider monoclonal antibody as monotherapy in immunocompromised patients as a risk for escape mutants selection.

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Section: Manuscriptmentioning

confidence: 99%

Sotrovimab drives SARS-CoV-2 Omicron variant evolution in immunocompromised patients

Destras

Bal

Simon

et al. 2022

Preprint

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“…Mutations within the RBD allow immune escape and increase transmissibility via enhanced receptor affinity. Rapid viral evolution has been observed after treatment with monoclonal antibody drugs, including the appearance of escape mutations to LY-CoV555 and VIR-7831 in immunocompromised (Jensen et al , 2021) and immunocompetent patients (Rockett et al , 2022). To minimize the likelihood of full escape, non-competing monoclonal antibodies are combined as cocktails with some success (Baum et al , 2020).…”

Section: Introductionmentioning

confidence: 99%

An engineered ACE2 decoy receptor can be administered by inhalation and potently targets the BA.1 and BA.2 omicron variants of SARS-CoV-2

Zhang

Narayanan

Cooper

et al. 2022

Preprint

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Monoclonal antibodies targeting the SARS-CoV-2 spike (S) glycoprotein neutralize infection and are efficacious for the treatment of mild-to-moderate COVID-19. However, SARS-CoV-2 variants have emerged that partially or fully escape monoclonal antibodies in clinical use. Notably, the BA.2 sublineage of B.1.1.529/omicron escapes nearly all monoclonal antibodies currently authorized for therapeutic treatment of COVID-19. Decoy receptors, which are based on soluble forms of the host entry receptor ACE2, are an alternative strategy that broadly bind and block S from SARS-CoV-2 variants and related betacoronaviruses. The high-affinity and catalytically active decoy sACE22.v2.4-IgG1 was previously shown to be effective in vivo against SARS-CoV-2 variants when administered intravenously. Here, the inhalation of sACE22.v2.4-IgG1 is found to increase survival and ameliorate lung injury in K18-hACE2 transgenic mice inoculated with a lethal dose of the virulent P.1/gamma virus. Loss of catalytic activity reduced the decoy's therapeutic efficacy supporting dual mechanisms of action: direct blocking of viral S and turnover of ACE2 substrates associated with lung injury and inflammation. Binding of sACE22.v2.4-IgG1 remained tight to S of BA.1 omicron, despite BA.1 omicron having extensive mutations, and binding exceeded that of four monoclonal antibodies approved for clinical use. BA.1 pseudovirus and authentic virus were neutralized at picomolar concentrations. Finally, tight binding was maintained against S from the BA.2 omicron sublineage, which differs from S of BA.1 by 26 mutations. Overall, the therapeutic potential of sACE22.v2.4-IgG1 is further confirmed by inhalation route and broad neutralization potency persists against increasingly divergent SARS-CoV-2 variants.

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“…Recently, the selection of mutations in the spike protein of the Delta VOC in 4 of 100 patients treated with sotrovimab was reported and all 4 were immunocompromised. 6 Specifically, mutations at position 337 and 340 known to reduce susceptibility to sotrovimab were found. 7 We studied viral evolution in 47 immunocompromised patients treated with sotrovimab for an infection with the Omicron VOC.…”

Section: Introductionmentioning

confidence: 99%

High incidence of sotrovimab resistance and viral persistence after treatment of immunocompromised patients infected with the SARS-CoV-2 Omicron variant

Huygens

Munnink

Gharbharan

et al. 2022

Preprint

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BackgroundSotrovimab is a monoclonal antibody that neutralizes SARS-CoV-2 by binding to a highly conserved epitope in the receptor binding domain. It retains activity against the Omicron BA.1 variant and is used to treat immunocompromised patients as they are at increased risk for a severe outcome of COVID-19.MethodsWe studied viral evolution in 47 immunocompromised patients infected with Omicron BA.1 or 2 and treated with sotrovimab. SARS-CoV-2 PCR was performed at baseline and weekly thereafter until Ct-value was ≥ 30. All RNA samples were sequenced to determine the variant and occurrence of mutations, in particular in the Spike protein, after treatment.ResultsTwenty-four (51%) of the 47 patients were male and their median age was 63 years. Thirty-one (66%) had undergone a solid organ transplantation and 13 (28%) had received prior B-cell depleting therapy. Despite a history of vaccination, 24 of 30 patients with available data on anti-SARS-CoV-2 IgG Spike antibodies prior to treatment with sotrovimab had very low or no antibodies. Median time to viral clearance (Ct-value ≥ 30) after treatment was 15 days (IQR 7-22). However, viral RNA with low Ct-values was continuously detected for at least 28 days after treatment in four patients infected with BA.1. Mutations in the Spike protein at position 337 or 340 were observed in all four patients. Similar mutations were also found after treatment of two patients with a BA.2 infection but both cleared the virus within two weeks. Thus following treatment with sotrovimab, spike mutations associated with reduced in vitro susceptibility were detected in 6 of 47 (13%) patients.ConclusionViral evolution towards resistance against sotrovimab can explain treatment failure in most immunocompromised patients and these patients can remain infectious after treatment. Therefore, documenting viral clearance after treatment is recommended to avoid that these patients unintentionally become a source of new, sotrovimab resistant, variants. Research on direct acting antivirals and possibly combination therapy for the treatment of COVID-19 in immunocompromised patients is needed.

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Resistance Mutations in SARS-CoV-2 Delta Variant after Sotrovimab Use

Cited by 163 publications

References 5 publications

Sotrovimab drives SARS-CoV-2 Omicron variant evolution in immunocompromised patients

Sotrovimab drives SARS-CoV-2 Omicron variant evolution in immunocompromised patients

An engineered ACE2 decoy receptor can be administered by inhalation and potently targets the BA.1 and BA.2 omicron variants of SARS-CoV-2

High incidence of sotrovimab resistance and viral persistence after treatment of immunocompromised patients infected with the SARS-CoV-2 Omicron variant

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