TY - JOUR
T1 - Emergence of Delta and Omicron variants carrying resistance-associated mutations in immunocompromised patients undergoing sotrovimab treatment with long-term viral excretion
AU - Andrés, Cristina
AU - González-Sánchez, Alejandra
AU - Jiménez, Moraima
AU - Márquez-Algaba, Ester
AU - Piñana, Maria
AU - Fernández-Naval, Candela
AU - Esperalba, Juliana
AU - Saubi, Narcís
AU - Quer, Josep
AU - Rando-Segura, Ariadna
AU - Miarons, Marta
AU - Codina, Maria Gema
AU - Ruiz-Camps, Isabel
AU - Pumarola, Tomàs
AU - Abrisqueta, Pau
AU - Antón, Andrés
N1 - Publisher Copyright:
© 2022 European Society of Clinical Microbiology and Infectious Diseases
PY - 2023/2
Y1 - 2023/2
N2 - Objectives: To monitor the early emergence of genetic mutations related to reduced susceptibility to monoclonal anti-body (mAb)-based treatment in immunocompromised patients with long-term viral excretion using whole-genome sequencing at a tertiary university hospital in Barcelona, Spain. Methods: Serial severe acute respiratory syndrome coronavirus 2-positive samples (mid-December 2021–mid-March 2022) from eight immunosuppressed, fully vaccinated patients (for solid-organ transplantation or haematologic malignancies) with long-term viral excretion despite undergoing mAb therapy (sotrovimab) for coronavirus disease 2019 were selected. Whole-genome sequencing was performed following the ARTIC, version 4.1, protocol on the MiSeq platform. Mutations in the coding sequence of the spike protein with a frequency of ≥5% were studied. Results: A total of 37 samples from the studied cases were analysed. All the cases, except one, were confirmed to have the Omicron variant BA.1; one had Delta (AY.100). Thirty-four different mutations were detected within the receptor-binding domain of the spike protein in 62.5% of patients, eight of which were not lineage related and located in the sotrovimab target epitope (P337L, E340D, E340R, E340K, E340V, E340Q, R346T and K356T). Except for P337L, all changes showed a significant increase in frequency or fixation after the administration of sotrovimab. Some of them have been associated with either reduced susceptibility to mAb therapy, such as those at position 340, or the acquisition of a new glycosylation site (346 and 356 positions). Conclusions: This study highlights the importance of monitoring for early in vivo selection of mutations associated with reduced susceptibility to mAb therapy, especially in immunocompromised patients receiving anti-viral drugs, whose immune response is not able to control viral replication, resulting in long-term viral shedding, and those receiving selective evolution pressure. Virologic surveillance of genetically resistant viruses to available anti-viral therapies is considered a priority for both patients and the community.
AB - Objectives: To monitor the early emergence of genetic mutations related to reduced susceptibility to monoclonal anti-body (mAb)-based treatment in immunocompromised patients with long-term viral excretion using whole-genome sequencing at a tertiary university hospital in Barcelona, Spain. Methods: Serial severe acute respiratory syndrome coronavirus 2-positive samples (mid-December 2021–mid-March 2022) from eight immunosuppressed, fully vaccinated patients (for solid-organ transplantation or haematologic malignancies) with long-term viral excretion despite undergoing mAb therapy (sotrovimab) for coronavirus disease 2019 were selected. Whole-genome sequencing was performed following the ARTIC, version 4.1, protocol on the MiSeq platform. Mutations in the coding sequence of the spike protein with a frequency of ≥5% were studied. Results: A total of 37 samples from the studied cases were analysed. All the cases, except one, were confirmed to have the Omicron variant BA.1; one had Delta (AY.100). Thirty-four different mutations were detected within the receptor-binding domain of the spike protein in 62.5% of patients, eight of which were not lineage related and located in the sotrovimab target epitope (P337L, E340D, E340R, E340K, E340V, E340Q, R346T and K356T). Except for P337L, all changes showed a significant increase in frequency or fixation after the administration of sotrovimab. Some of them have been associated with either reduced susceptibility to mAb therapy, such as those at position 340, or the acquisition of a new glycosylation site (346 and 356 positions). Conclusions: This study highlights the importance of monitoring for early in vivo selection of mutations associated with reduced susceptibility to mAb therapy, especially in immunocompromised patients receiving anti-viral drugs, whose immune response is not able to control viral replication, resulting in long-term viral shedding, and those receiving selective evolution pressure. Virologic surveillance of genetically resistant viruses to available anti-viral therapies is considered a priority for both patients and the community.
KW - Immunocompromised
KW - Omicron
KW - Resistance
KW - SARS-CoV-2
KW - Sotrovimab
KW - Antibodies, Neutralizing
KW - SARS-CoV-2/genetics
KW - Humans
KW - Virus Shedding/genetics
KW - Antibodies, Viral
KW - Spike Glycoprotein, Coronavirus/genetics
KW - Drug Resistance, Viral/genetics
KW - COVID-19/genetics
KW - Mutation
KW - Immunocompromised Host/immunology
UR - http://www.scopus.com/inward/record.url?scp=85138812846&partnerID=8YFLogxK
U2 - 10.1016/j.cmi.2022.08.021
DO - 10.1016/j.cmi.2022.08.021
M3 - Article
C2 - 36067943
AN - SCOPUS:85138812846
SN - 1198-743X
VL - 29
SP - 240
EP - 246
JO - Clinical Microbiology and Infection
JF - Clinical Microbiology and Infection
IS - 2
ER -