De novo emergence of SARS-CoV-2 spike mutations in immunosuppressed patients

Lacy M. Simons; Egon A. Ozer; Stephanie Gambut; Taylor J. Dean; Li Zhang; Pavan Bhimalli; Jeffrey R. Schneider; João I. Mamede; Michael G. Ison; Reem Karmali; Leo I. Gordon; Ramon Lorenzo-Redondo; Judd F. Hultquist

doi:10.1111/tid.13914

De novo emergence of SARS-CoV-2 spike mutations in immunosuppressed patients

Lacy M. Simons, Egon A. Ozer, Stephanie Gambut, Taylor J. Dean, Li Zhang, Pavan Bhimalli, Jeffrey R. Schneider, João I. Mamede, Michael G. Ison, Reem Karmali, Leo I. Gordon, Ramon Lorenzo-Redondo, Judd F. Hultquist^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

13 Scopus citations

Abstract

Background: The continuing evolution of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants with decreased susceptibility to neutralizing antibodies is of clinical importance. Several spike mutations associated with immune escape have evolved independently in association with different variants of concern (VOCs). How and when these mutations arise is still unclear. We hypothesized that such mutations might arise in the context of persistent viral replication in immunosuppressed hosts. Methods: Nasopharyngeal specimens were collected longitudinally from two immunosuppressed patients with persistent SARS-CoV-2 infection. Plasma was collected from these same patients late in disease course. SARS-CoV-2 whole genome sequencing was performed to assess the emergence and frequency of mutations over time. Select Spike mutations were assessed for their impact on viral entry and antibody neutralization in vitro. Results: Our sequencing results revealed the intrahost emergence of spike mutations that are associated with circulating VOCs in both immunosuppressed patients (del241-243 and E484Q in one patient, and E484K in the other). These mutations decreased antibody-mediated neutralization of pseudotyped virus particles in cell culture, but also decreased efficiency of spike-mediated cell entry. Conclusions: These observations demonstrate the de novo emergence of SARS-CoV-2 spike mutations with enhanced immune evasion in immunosuppressed patients with persistent infection. These data suggest one potential mechanism for the evolution of VOCs and emphasize the importance of continued efforts to develop antiviral drugs for suppression of viral replication in hospitalized settings.

Original language	English (US)
Article number	e13914
Journal	Transplant Infectious Disease
Volume	24
Issue number	6
DOIs	https://doi.org/10.1111/tid.13914
State	Published - Dec 2022

Funding

Supported by grants (R21 AI163912, to Dr. Hultquist, U19 AI135964, to Dr. Ozer) from the National Institutes of Health; a grant (to Dr. Lorenzo‐Redondo) from the Northwestern University Havey Institute for Global Health; a pilot award (to Dr. Ison) from the Northwestern University Clinical and Translational Science Institute; an internal award (to Dr. Mamede) from Rush University; and by grants (SCI16 and 21–00147, to Dr. Schneider) from the Walder Foundation's Chicago Coronavirus Assessment Network. This research was supported in part through the computational resources and staff contributions provided for the Quest high performance computing facility at Northwestern University, which is jointly supported by the Office of the Provost, the Office for Research, and Northwestern University Information Technology. Clinical data collection was supported in part by the Northwestern Medicine Enterprise Data Warehouse. The funding sources had no role in the study design, data collection, analysis, interpretation, or writing of the report.

Keywords

COVID-19
SARS-CoV-2
immunosuppressed
persistent infection
spike mutation
variants of concern
viral evolution

ASJC Scopus subject areas

Transplantation
Infectious Diseases

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1111/tid.13914

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title = "De novo emergence of SARS-CoV-2 spike mutations in immunosuppressed patients",

abstract = "Background: The continuing evolution of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants with decreased susceptibility to neutralizing antibodies is of clinical importance. Several spike mutations associated with immune escape have evolved independently in association with different variants of concern (VOCs). How and when these mutations arise is still unclear. We hypothesized that such mutations might arise in the context of persistent viral replication in immunosuppressed hosts. Methods: Nasopharyngeal specimens were collected longitudinally from two immunosuppressed patients with persistent SARS-CoV-2 infection. Plasma was collected from these same patients late in disease course. SARS-CoV-2 whole genome sequencing was performed to assess the emergence and frequency of mutations over time. Select Spike mutations were assessed for their impact on viral entry and antibody neutralization in vitro. Results: Our sequencing results revealed the intrahost emergence of spike mutations that are associated with circulating VOCs in both immunosuppressed patients (del241-243 and E484Q in one patient, and E484K in the other). These mutations decreased antibody-mediated neutralization of pseudotyped virus particles in cell culture, but also decreased efficiency of spike-mediated cell entry. Conclusions: These observations demonstrate the de novo emergence of SARS-CoV-2 spike mutations with enhanced immune evasion in immunosuppressed patients with persistent infection. These data suggest one potential mechanism for the evolution of VOCs and emphasize the importance of continued efforts to develop antiviral drugs for suppression of viral replication in hospitalized settings.",

keywords = "COVID-19, SARS-CoV-2, immunosuppressed, persistent infection, spike mutation, variants of concern, viral evolution",

author = "Simons, {Lacy M.} and Ozer, {Egon A.} and Stephanie Gambut and Dean, {Taylor J.} and Li Zhang and Pavan Bhimalli and Schneider, {Jeffrey R.} and Mamede, {Jo{\~a}o I.} and Ison, {Michael G.} and Reem Karmali and Gordon, {Leo I.} and Ramon Lorenzo-Redondo and Hultquist, {Judd F.}",

note = "Publisher Copyright: {\textcopyright} 2022 The Authors. Transplant Infectious Disease published by Wiley Periodicals LLC.",

year = "2022",

month = dec,

doi = "10.1111/tid.13914",

language = "English (US)",

volume = "24",

journal = "Transplant Infectious Disease",

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T1 - De novo emergence of SARS-CoV-2 spike mutations in immunosuppressed patients

AU - Simons, Lacy M.

AU - Ozer, Egon A.

AU - Gambut, Stephanie

AU - Dean, Taylor J.

AU - Zhang, Li

AU - Bhimalli, Pavan

AU - Schneider, Jeffrey R.

AU - Mamede, João I.

AU - Ison, Michael G.

AU - Karmali, Reem

AU - Gordon, Leo I.

AU - Lorenzo-Redondo, Ramon

AU - Hultquist, Judd F.

PY - 2022/12

Y1 - 2022/12

N2 - Background: The continuing evolution of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants with decreased susceptibility to neutralizing antibodies is of clinical importance. Several spike mutations associated with immune escape have evolved independently in association with different variants of concern (VOCs). How and when these mutations arise is still unclear. We hypothesized that such mutations might arise in the context of persistent viral replication in immunosuppressed hosts. Methods: Nasopharyngeal specimens were collected longitudinally from two immunosuppressed patients with persistent SARS-CoV-2 infection. Plasma was collected from these same patients late in disease course. SARS-CoV-2 whole genome sequencing was performed to assess the emergence and frequency of mutations over time. Select Spike mutations were assessed for their impact on viral entry and antibody neutralization in vitro. Results: Our sequencing results revealed the intrahost emergence of spike mutations that are associated with circulating VOCs in both immunosuppressed patients (del241-243 and E484Q in one patient, and E484K in the other). These mutations decreased antibody-mediated neutralization of pseudotyped virus particles in cell culture, but also decreased efficiency of spike-mediated cell entry. Conclusions: These observations demonstrate the de novo emergence of SARS-CoV-2 spike mutations with enhanced immune evasion in immunosuppressed patients with persistent infection. These data suggest one potential mechanism for the evolution of VOCs and emphasize the importance of continued efforts to develop antiviral drugs for suppression of viral replication in hospitalized settings.

AB - Background: The continuing evolution of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants with decreased susceptibility to neutralizing antibodies is of clinical importance. Several spike mutations associated with immune escape have evolved independently in association with different variants of concern (VOCs). How and when these mutations arise is still unclear. We hypothesized that such mutations might arise in the context of persistent viral replication in immunosuppressed hosts. Methods: Nasopharyngeal specimens were collected longitudinally from two immunosuppressed patients with persistent SARS-CoV-2 infection. Plasma was collected from these same patients late in disease course. SARS-CoV-2 whole genome sequencing was performed to assess the emergence and frequency of mutations over time. Select Spike mutations were assessed for their impact on viral entry and antibody neutralization in vitro. Results: Our sequencing results revealed the intrahost emergence of spike mutations that are associated with circulating VOCs in both immunosuppressed patients (del241-243 and E484Q in one patient, and E484K in the other). These mutations decreased antibody-mediated neutralization of pseudotyped virus particles in cell culture, but also decreased efficiency of spike-mediated cell entry. Conclusions: These observations demonstrate the de novo emergence of SARS-CoV-2 spike mutations with enhanced immune evasion in immunosuppressed patients with persistent infection. These data suggest one potential mechanism for the evolution of VOCs and emphasize the importance of continued efforts to develop antiviral drugs for suppression of viral replication in hospitalized settings.

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ER -

De novo emergence of SARS-CoV-2 spike mutations in immunosuppressed patients

Abstract

Funding

Keywords

ASJC Scopus subject areas

UN SDGs

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