Emergence of Delta and Omicron variants carrying resistance-associated mutations in immunocompromised patients undergoing sotrovimab treatment with long-term viral excretion

Andrés, Cristina; González-Sánchez, Alejandra; Jiménez, Moraima; Márquez-Algaba, Ester; Piñana, María; Fernández‐Naval, Candela; Esperalba, Juliana; Saubí, Narcís; Quer, Josep; Rando‐Segura, Ariadna; Miarons, Marta; Codina, María Gema; Ruiz‐Camps, Isabel; Pumarola, Tomás; Antón, Andrés

doi:10.1016/j.cmi.2022.08.021

Cited by 23 publications

(22 citation statements)

References 19 publications

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“…All 14 mutations that became fixed corresponded to either P337 or E340 (5 and 9, respectively), with the most frequent being E340K (4 times), followed by E340D and P337S (3 times each), E340Q (twice) and P337L and P337R, identified only once each. These substitutions are also found at high rates in other studies (5)(6)(7)(8)10). More than one different fixed substitution never cooccurred in the same specimen.…”

Section: Dynamics Of Resistance Mutationssupporting

confidence: 74%

“…Resistance mutations were detected in 15 patients (68%), which places our findings above the highest frequencies (55%-60%) reported to date (5,6). The mutations identified (frequency >5%) were distributed among the four codons previously described to encode sotrovimab resistance (P337, E340, R346 and K356) and included 14 different substitutions (P337S/R/T/L/A/H, E340Q/A/D/K/V/G, R346T and K356T).…”

Section: Emergence Of Resistance Mutationssupporting

confidence: 58%

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Frequent emergence of resistance mutations following complex intra-host genomic dynamics in SARS-CoV-2 patients receiving Sotrovimab

Palomino-Cabrera

Tejerina

Molero-Salinas

et al. 2023

Preprint

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The emergence of the Omicron variant of SARS-CoV-2 represented a challenge to the treatment of COVID-19 with monoclonal antibodies. Only Sotrovimab maintained partial activity, allowing it to be used in high-risk patients infected with the Omicron variant. However, the reports of resistance mutations to Sotrovimab call for efforts to better understand the intra-patient emergence of this resistance. A retrospective genomic analysis was conducted on respiratory samples from immunocompromised patients infected with SARS-CoV-2 who received Sotrovimab at our hospital between December 2021 and August 2022. The study involved 95 sequential specimens from 22 patients (1-12 samples/patient; 3-107 days post-infusion (Ct ≤ 32)). Resistance mutations (in P337, E340, K356, and R346) were detected in 68% of cases; the shortest time to detection of a resistance mutation was 5 days after Sotrovimab infusion. The dynamics of resistance acquisition were highly complex, with up to 11 distinct amino acid changes in specimens from the same patient. In two patients, the mutation distribution was compartmentalized in respiratory samples from different sources. This is the first study to examine the acquisition of resistance to Sotrovimab in the BA.5 lineage, enabling us to determine the lack of genomic or clinical differences between Sotrovimab resistance in BA.5 relative to BA.1/2. Across all Omicron lineages, the acquisition of resistance delayed SARS-CoV-2 clearance (40.67 vs 19.5 days). Close, real-time genomic surveillance of patients receiving Sotrovimab should be mandatory to facilitate early therapeutic interventions.

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Section: Dynamics Of Resistance Mutationssupporting

confidence: 74%

Section: Emergence Of Resistance Mutationssupporting

confidence: 58%

Frequent emergence of resistance mutations following complex intra-host genomic dynamics in SARS-CoV-2 patients receiving Sotrovimab

Palomino-Cabrera

Tejerina

Molero-Salinas

et al. 2023

Preprint

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“…Lee et al reported mutually exclusive substitutions at residues R346 (R346S and R346I) and E484 (E484K and E484A) of Spike protein and continuous turnover of these substitutions in 2 immunosuppressed patients[39]. Unfortunately, in vivo selection evidences are so far available for sotrovimab[40] but not for Evusheld™. It should be anyway noted that R346T[41,42] and R346I[43] have been reported to spontaneously develop and fix in 3 IC patients without any selective pressure.…”

Section: Introductionmentioning

confidence: 99%

Convergent evolution in SARS-CoV-2 Spike creates a variant soup that causes new COVID-19 waves

Focosi¹,

Quiroga

McConnell

et al. 2022

Preprint

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The first 2 years of the COVID-19 pandemic were mainly characterized by convergent evolution of mutations of SARS-CoV-2 Spike protein at residues K417, L452, E484, N501 and P681 across different variants of concern (Alpha, Beta, Gamma, and Delta). Since Spring 2022 and the third year of the pandemic, with the advent of Omicron and its sublineages, convergent evolution has led to the observation of different lineages acquiring an additional group of mutations at different amino acid residues, namely R346, K444, N450, N460, F486, F490, Q493, and S494. Mutations at these residues have become increasingly prevalent during Summer and Autumn 2022, with combinations showing increased fitness. The most likely reason for this convergence is the selective pressure exerted by previous infection- or vaccine-elicited immunity. Such accelerated evolution has caused failure of all anti-Spike monoclonal antibodies, including bebtelovimab and cilgavimab. While we are learning how fast coronaviruses can mutate and recombine, we should reconsider opportunities for economically sustainable escape-proof combination therapies, and reevaluate the potential for polyclonal therapies (such as COVID19 convalescent plasma) in immunocompromised patients.

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“…Whole viral genome sequencing revealed Spike mutations (L5F, Y145D, E340A, L582F, F855L, and L938F) after receiving sotrovimab, as shown in Supplementary Table 2 (GISAID accession EPI_ISL_16849243, EPI_ISL_16849243, EPI_ISL_16849245). Notably, S:E340A confers immune escape to sotrovimab [2] , [3] , [4] , [5] , [6] , [7] , [8] , [9] , [10] , [11] , [12] . We also observed an overall reduction in the number of S epitopes that could be presented by the patient's HLA alleles, as depicted in Supplementary Materials.…”

Section: Dear Editormentioning

confidence: 99%

SARS-CoV-2 evolution during persistent infection in a CAR-T recipient shows an escape to both sotrovimab and T-cell responses

Mazzetti¹,

Spezia²,

Capria³

et al. 2023

Journal of Clinical Virology Plus

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Emergence of Delta and Omicron variants carrying resistance-associated mutations in immunocompromised patients undergoing sotrovimab treatment with long-term viral excretion

Cited by 23 publications

References 19 publications

Frequent emergence of resistance mutations following complex intra-host genomic dynamics in SARS-CoV-2 patients receiving Sotrovimab

Frequent emergence of resistance mutations following complex intra-host genomic dynamics in SARS-CoV-2 patients receiving Sotrovimab

Convergent evolution in SARS-CoV-2 Spike creates a variant soup that causes new COVID-19 waves

SARS-CoV-2 evolution during persistent infection in a CAR-T recipient shows an escape to both sotrovimab and T-cell responses

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