Evolution of a globally unique SARS-CoV-2 Spike E484T monoclonal antibody escape mutation in a persistently infected, immunocompromised individual

Halfmann, Peter; Minor, Nicholas R.; Haddock, Luis A; Maddox, Robert James; Moreno, Gage K.; Braun, Katarina M.; Baker, David; Riemersa, Kasen K; Prasad, A. Mallikarjuna; Alman, Kirsten J.; Lambert, Matthew C.; Florek, Kelsey; Bateman, Allen C.; Westergaard, Ryan P.; Safdar, Nasia; Andes, David R.; Kawaoka, Yoshihiro; Fida, Madiha; Yao, Joseph D.; Friedrich, Thomas C.; O’Connor, David H.

doi:10.1093/ve/veac104

Cited by 19 publications

(8 citation statements)

References 62 publications

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“…Specifically, P29 who had only molnupiravir treatment showed multiple nsp3 and spike substitutions that were caused by G to A or C to T nucleotide changes, which corresponds to the antiviral mechanisms of molnupiravir [ 29 , 45 ]; this includes G23012A that led to the double codon mutation S:E484T, a derivative of E484A in the 1st sampling. Recently, E484T has been reported by Halfmann et al [ 28 ] in a persistently infected immunosuppressed individual in response to mAb treatment (bamlanivimab), where the mutation also progressed from E484A. Together with our study, these findings support the concept that the convergent immune-escaping mutations could be derived from different types of antiviral therapies, and highlight the importance of delineating the correlation between antiviral treatment and immune-escape viral mutations.…”

Section: Discussionsupporting

confidence: 88%

Evidence of SARS-CoV-2 convergent evolution in immunosuppressed patients treated with antiviral therapies

Feng,

Reid,

Clark

et al. 2024

Virol J

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Background The factors contributing to the accelerated convergent evolution of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are not fully understood. Unraveling the contribution of viral replication in immunocompromised patients is important for the early detection of novel mutations and developing approaches to limit COVID-19. Methods We deep sequenced SARS-CoV-2 RNA from 192 patients (64% hospitalized, 39% immunosuppressed) and compared the viral genetic diversity within the patient groups of different immunity and hospitalization status. Serial sampling of 14 patients was evaluated for viral evolution in response to antiviral treatments. Results We identified hospitalized and immunosuppressed patients with significantly higher levels of viral genetic diversity and variability. Further evaluation of serial samples revealed accumulated mutations associated with escape from neutralizing antibodies in a subset of the immunosuppressed patients treated with antiviral therapies. Interestingly, the accumulated viral mutations that arose in this early Omicron wave, which were not common in the patient viral lineages, represent convergent mutations that are prevalent in the later Omicron sublineages, including the XBB, BA.2.86.1 and its descendent JN sublineages. Conclusions Our results illustrate the importance of identifying convergent mutations generated during antiviral therapy in immunosuppressed patients, as they may contribute to the future evolutionary landscape of SARS-CoV-2. Our study also provides evidence of a correlation between SARS-CoV-2 convergent mutations and specific antiviral treatments. Evaluating high-confidence genomes from distinct waves in the pandemic with detailed patient metadata allows for discerning of convergent mutations that contribute to the ongoing evolution of SARS-CoV-2.

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Section: Discussionsupporting

confidence: 88%

Evidence of SARS-CoV-2 convergent evolution in immunosuppressed patients treated with antiviral therapies

Feng,

Reid,

Clark

et al. 2024

Virol J

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“…In our case study, we detected different mutations that are concerning because of their relationship with immune system evasion, such as ORF1ab:T1638I (NSP3), ORF1ab:S1188L (NSP3) and ORF3a:Q213K [23,24]. We also found mutations previously found in within-host evolution analyses such as N:P383L, ORF1ab:H1213Y (NSP13) and S:V143D + ΔY144 [25][26][27].…”

Section: Discussionsupporting

confidence: 65%

VIPERA: Viral Intra-Patient Evolution Reporting and Analysis

Álvarez-Herrera,

Sevilla,

Ruiz-Rodriguez

et al. 2023

Preprint

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Viral mutations within patients nurture the adaptive potential of SARS-CoV-2 during chronic infections, which are a potential source of variants of concern. However, there is no integrated framework for the evolutionary analysis of intra-patient SARS-CoV-2 serial samples. Herein we describe VIPERA (Viral Intra-Patient Evolution Reporting and Analysis), a new software that integrates the evaluation of the intra-patient ancestry of SARS-CoV-2 sequences with the analysis of evolutionary trajectories of serial sequences from the same viral infection. It has been validated using positive and negative control datasets and successfully applied to a novel case, contributing to easy and automatic analysis of intra-patient SARS-CoV-2 sequences.

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“…For these exploratory analyses, 13 uncontrolled large case series without individual patient data enrolling 358 participants were included in descriptive analysis . In this study, 125 case reports or case series enrolling 265 participants were included for patient-level exploratory analyses. One study was included in both the descriptive analysis and the individual patient data analysis because individual patient data were available only for a subgroup of patients.…”

Section: Resultsmentioning

confidence: 99%

COVID-19 Convalescent Plasma for the Treatment of Immunocompromised Patients: A Systematic Review and Meta-analysis

et al. 2023

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ImportancePatients who are immunocompromised have increased risk for morbidity and mortality associated with coronavirus disease 2019 (COVID-19) because they less frequently mount antibody responses to vaccines. Although neutralizing anti-spike monoclonal-antibody treatment has been widely used to treat COVID-19, evolutions of SARS-CoV-2 have been associated with monoclonal antibody-resistant SARS-CoV-2 variants and greater virulence and transmissibility of SARS-CoV-2. Thus, the therapeutic use of COVID-19 convalescent plasma has increased on the presumption that such plasma contains potentially therapeutic antibodies to SARS-CoV-2 that can be passively transferred to the plasma recipient.ObjectiveTo assess the growing number of reports of clinical experiences of patients with COVID-19 who are immunocompromised and treated with specific neutralizing antibodies via COVID-19 convalescent plasma transfusion.Data SourcesOn August 12, 2022, a systematic search was performed for clinical studies of COVID-19 convalescent plasma use in patients who are immunocompromised.Study SelectionRandomized clinical trials, matched cohort studies, and case report or series on COVID-19 convalescent plasma use in patients who are immunocompromised were included. The electronic search yielded 462 unique records, of which 199 were considered for full-text screening.Data Extraction and SynthesisThe study followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Data were extracted by 3 independent reviewers in duplicate and pooled.Main Outcomes and MeauresThe prespecified end point was all-cause mortality after COVID-19 convalescent plasma transfusion; exploratory subgroup analyses were performed based on putative factors associated with the potential mortality benefit of convalescent plasma.ResultsThis systematic review and meta-analysis included 3 randomized clinical trials enrolling 1487 participants and 5 controlled studies. Additionally, 125 case series or reports enrolling 265 participants and 13 uncontrolled large case series enrolling 358 participants were included. Separate meta-analyses, using models both stratified and pooled by study type (ie, randomized clinical trials and matched cohort studies), demonstrated that transfusion of COVID-19 convalescent plasma was associated with a decrease in mortality compared with the control cohort for the amalgam of both randomized clinical trials and matched cohort studies (risk ratio [RR], 0.63 [95% CI, 0.50-0.79]).Conclusions and RelevanceThese findings suggest that transfusion of COVID-19 convalescent plasma is associated with mortality benefit for patients who are immunocompromised and have COVID-19.

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Evolution of a globally unique SARS-CoV-2 Spike E484T monoclonal antibody escape mutation in a persistently infected, immunocompromised individual

Cited by 19 publications

References 62 publications

Evidence of SARS-CoV-2 convergent evolution in immunosuppressed patients treated with antiviral therapies

Evidence of SARS-CoV-2 convergent evolution in immunosuppressed patients treated with antiviral therapies

VIPERA: Viral Intra-Patient Evolution Reporting and Analysis

COVID-19 Convalescent Plasma for the Treatment of Immunocompromised Patients: A Systematic Review and Meta-analysis

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