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Emergence of Multiple SARS-CoV-2 Antibody Escape Variants in an Immunocompromised Host Undergoing Convalescent Plasma Treatment.
mSphere. 2021 08 25; 6(4):e0048021.M

Abstract

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants of concern (VOCs), harboring spike protein N-terminal domain (NTD) or receptor-binding domain (RBD) mutations, exhibit reduced in vitro susceptibility to convalescent-phase serum, commercial antibody cocktails, and vaccine neutralization and have been associated with reinfections. The accumulation of these mutations could be the consequence of intrahost viral evolution due to prolonged infection in immunocompromised hosts. In this study, we document the microevolution of SARS-CoV-2 recovered from sequential tracheal aspirates from an immunosuppressed patient on steroids and convalescent plasma therapy and identify the emergence of multiple NTD and RBD mutations. SARS-CoV-2 genomes from the first swab (day 0) and from three tracheal aspirates (days 7, 21, and 27) were compared at the sequence level. We identified a mixed viral population with five different S protein mutations (141 to 144 deletion, 243 to 244 deletion, E484K, Q493K, and Q493R) at the NTD or RBD region from the second tracheal aspirate sample (day 21) and a predominance of the S protein 141 to 144 LGVY deletion and E484K mutant on day 27. The neutralizing antibodies against various S protein lentiviral pseudovirus mutants, as well as the anti-SARS-CoV-2 total Ig and IgG, showed "U" shape dynamics, in support of the endogenous development of neutralizing antibodies. The patient's compromised immune status, the antirejection regiment, convalescent plasma treatment, and the development of neutralizing antibodies may have resulted in unique selective pressures on the intrahost genomic evolution, and this observation supports the hypotheses that VOCs can independently arise and that immunocompromised patients on convalescent plasma therapy are potential breeding grounds for immune escape mutants. IMPORTANCE Over a year of the COVID-19 pandemic, distinct severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) lineages have arisen in multiple geographic areas around the world. SARS-CoV-2 variants of concern (VOCs), i.e., B.1.1.7 (alpha), B.1.351 (beta), P.1 (gamma), and B.1.617.2 (delta), harboring mutations and/or deletions in spike protein N-terminal domain (NTD) or receptor-binding domain (RBD) regions showed evidence of increased transmissibility and disease severity and possible reduced vaccine efficacy. In this study, we report the emergence of five different NTD and RBD mutations in an uncommon SARS-CoV-2 B.1.369 lineage from an immunosuppressed patient undergoing steroid and convalescent plasma therapy. The observation highlighted that VOCs can independently arise in immunocompromised populations undergoing anti-SARS-CoV-2 therapy, and enhanced measures will be required to reduce the transmission.

Authors+Show Affiliations

Hackensack Meridian Health Center for Discovery and Innovation, Nutley, New Jersey, USA. Hackensack Meridian School of Medicine, Nutley, New Jersey, USA.New York Genome Centergrid.429884.b, New York, New York, USA.Vitalant Research Institute, San Francisco, California, USA.Vitalant Research Institute, San Francisco, California, USA.Hackensack Meridian Health Center for Discovery and Innovation, Nutley, New Jersey, USA.Hackensack Meridian Health Center for Discovery and Innovation, Nutley, New Jersey, USA.Hackensack Meridian Health Center for Discovery and Innovation, Nutley, New Jersey, USA.Hackensack Medical University Center, Hackensack, New Jersey, USA.Hackensack Meridian Health Center for Discovery and Innovation, Nutley, New Jersey, USA.New York Genome Centergrid.429884.b, New York, New York, USA.New York Genome Centergrid.429884.b, New York, New York, USA.New York Genome Centergrid.429884.b, New York, New York, USA.Hackensack Medical University Center, Hackensack, New Jersey, USA.Hackensack Medical University Center, Hackensack, New Jersey, USA.Hackensack Medical University Center, Hackensack, New Jersey, USA.Mailman School of Public Health, Columbia Universitygrid.21729.3f Irving Medical Center, New York, New York, USA.New York Genome Centergrid.429884.b, New York, New York, USA.Vitalant Research Institute, San Francisco, California, USA.Vitalant Research Institute, San Francisco, California, USA.Vitalant Research Institute, San Francisco, California, USA.New York Genome Centergrid.429884.b, New York, New York, USA.Hackensack Meridian Health Center for Discovery and Innovation, Nutley, New Jersey, USA. Hackensack Meridian School of Medicine, Nutley, New Jersey, USA.Hackensack Meridian Health Center for Discovery and Innovation, Nutley, New Jersey, USA.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

34431691

Citation

Chen, Liang, et al. "Emergence of Multiple SARS-CoV-2 Antibody Escape Variants in an Immunocompromised Host Undergoing Convalescent Plasma Treatment." MSphere, vol. 6, no. 4, 2021, pp. e0048021.
Chen L, Zody MC, Di Germanio C, et al. Emergence of Multiple SARS-CoV-2 Antibody Escape Variants in an Immunocompromised Host Undergoing Convalescent Plasma Treatment. mSphere. 2021;6(4):e0048021.
Chen, L., Zody, M. C., Di Germanio, C., Martinelli, R., Mediavilla, J. R., Cunningham, M. H., Composto, K., Chow, K. F., Kordalewska, M., Corvelo, A., Oschwald, D. M., Fennessey, S., Zetkulic, M., Dar, S., Kramer, Y., Mathema, B., Germer, S., Stone, M., Simmons, G., ... Kreiswirth, B. N. (2021). Emergence of Multiple SARS-CoV-2 Antibody Escape Variants in an Immunocompromised Host Undergoing Convalescent Plasma Treatment. MSphere, 6(4), e0048021. https://doi.org/10.1128/mSphere.00480-21
Chen L, et al. Emergence of Multiple SARS-CoV-2 Antibody Escape Variants in an Immunocompromised Host Undergoing Convalescent Plasma Treatment. mSphere. 2021 08 25;6(4):e0048021. PubMed PMID: 34431691.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Emergence of Multiple SARS-CoV-2 Antibody Escape Variants in an Immunocompromised Host Undergoing Convalescent Plasma Treatment. AU - Chen,Liang, AU - Zody,Michael C, AU - Di Germanio,Clara, AU - Martinelli,Rachel, AU - Mediavilla,Jose R, AU - Cunningham,Marcus H, AU - Composto,Kaelea, AU - Chow,Kar Fai, AU - Kordalewska,Milena, AU - Corvelo,André, AU - Oschwald,Dayna M, AU - Fennessey,Samantha, AU - Zetkulic,Marygrace, AU - Dar,Sophia, AU - Kramer,Yael, AU - Mathema,Barun, AU - Germer,Soren, AU - Stone,Mars, AU - Simmons,Graham, AU - Busch,Michael P, AU - Maniatis,Tom, AU - Perlin,David S, AU - Kreiswirth,Barry N, Y1 - 2021/08/25/ PY - 2021/8/25/entrez PY - 2021/8/26/pubmed PY - 2021/9/18/medline KW - SARS-CoV-2 KW - convalescent plasma KW - immunosuppression KW - spike protein KW - variants of concern SP - e0048021 EP - e0048021 JF - mSphere JO - mSphere VL - 6 IS - 4 N2 - Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants of concern (VOCs), harboring spike protein N-terminal domain (NTD) or receptor-binding domain (RBD) mutations, exhibit reduced in vitro susceptibility to convalescent-phase serum, commercial antibody cocktails, and vaccine neutralization and have been associated with reinfections. The accumulation of these mutations could be the consequence of intrahost viral evolution due to prolonged infection in immunocompromised hosts. In this study, we document the microevolution of SARS-CoV-2 recovered from sequential tracheal aspirates from an immunosuppressed patient on steroids and convalescent plasma therapy and identify the emergence of multiple NTD and RBD mutations. SARS-CoV-2 genomes from the first swab (day 0) and from three tracheal aspirates (days 7, 21, and 27) were compared at the sequence level. We identified a mixed viral population with five different S protein mutations (141 to 144 deletion, 243 to 244 deletion, E484K, Q493K, and Q493R) at the NTD or RBD region from the second tracheal aspirate sample (day 21) and a predominance of the S protein 141 to 144 LGVY deletion and E484K mutant on day 27. The neutralizing antibodies against various S protein lentiviral pseudovirus mutants, as well as the anti-SARS-CoV-2 total Ig and IgG, showed "U" shape dynamics, in support of the endogenous development of neutralizing antibodies. The patient's compromised immune status, the antirejection regiment, convalescent plasma treatment, and the development of neutralizing antibodies may have resulted in unique selective pressures on the intrahost genomic evolution, and this observation supports the hypotheses that VOCs can independently arise and that immunocompromised patients on convalescent plasma therapy are potential breeding grounds for immune escape mutants. IMPORTANCE Over a year of the COVID-19 pandemic, distinct severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) lineages have arisen in multiple geographic areas around the world. SARS-CoV-2 variants of concern (VOCs), i.e., B.1.1.7 (alpha), B.1.351 (beta), P.1 (gamma), and B.1.617.2 (delta), harboring mutations and/or deletions in spike protein N-terminal domain (NTD) or receptor-binding domain (RBD) regions showed evidence of increased transmissibility and disease severity and possible reduced vaccine efficacy. In this study, we report the emergence of five different NTD and RBD mutations in an uncommon SARS-CoV-2 B.1.369 lineage from an immunosuppressed patient undergoing steroid and convalescent plasma therapy. The observation highlighted that VOCs can independently arise in immunocompromised populations undergoing anti-SARS-CoV-2 therapy, and enhanced measures will be required to reduce the transmission. SN - 2379-5042 UR - https://www.unboundmedicine.com/medline/citation/34431691/Emergence_of_Multiple_SARS_CoV_2_Antibody_Escape_Variants_in_an_Immunocompromised_Host_Undergoing_Convalescent_Plasma_Treatment_ DB - PRIME DP - Unbound Medicine ER -