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Cross-Neutralization of Emerging SARS-CoV-2 Variants of Concern by Antibodies Targeting Distinct Epitopes on Spike.
mBio. 2021 12 21; 12(6):e0297521.MBIO

Abstract

Several severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants have arisen that exhibit increased viral transmissibility and partial evasion of immunity induced by natural infection and vaccination. To address the specific antibody targets that were affected by recent viral variants, we generated 43 monoclonal antibodies (mAbs) from 10 convalescent donors that bound three distinct domains of the SARS-CoV-2 spike. Viral variants harboring mutations at K417, E484, and N501 could escape most of the highly potent antibodies against the receptor binding domain (RBD). Despite this, we identified 12 neutralizing mAbs against three distinct regions of the spike protein that neutralize SARS-CoV-2 and variants of concern (VOCs), including B.1.1.7 (alpha), P.1 (gamma), and B.1.617.2 (delta). Notably, antibodies targeting distinct epitopes could neutralize discrete variants, suggesting that different variants may have evolved to disrupt the binding of particular neutralizing antibody classes. These results underscore that humans exposed to the first pandemic wave of prototype SARS-CoV-2 possess neutralizing antibodies against current variants and that it is critical to induce antibodies targeting multiple distinct epitopes of the spike that can neutralize emerging variants of concern. IMPORTANCE We describe the binding and neutralization properties of a new set of human monoclonal antibodies derived from memory B cells of 10 coronavirus disease 2019 (COVID-19) convalescent donors in the first pandemic wave of prototype SARS-CoV-2. There were 12 antibodies targeting distinct epitopes on spike, including two sites on the RBD and one on the N-terminal domain (NTD), that displayed cross-neutralization of VOCs, for which distinct antibody targets could neutralize discrete variants. This work underlines that natural infection by SARS-CoV-2 induces effective cross-neutralization against only some VOCs and supports the need for COVID-19 vaccination for robust induction of neutralizing antibodies targeting multiple epitopes of the spike protein to combat the current SARS-CoV-2 VOCs and any others that might emerge in the future.

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Authors+Show Affiliations

Changrob S
University of Chicagogrid.170205.1 Department of Medicine, Section of Rheumatology, Chicago, Illinois, USA.
Fu Y
University of Chicagogrid.170205.1 Department of Medicine, Section of Rheumatology, Chicago, Illinois, USA.
Guthmiller JJ
University of Chicagogrid.170205.1 Department of Medicine, Section of Rheumatology, Chicago, Illinois, USA.
Halfmann PJ
Influenza Research Institute, Department of Pathobiological Sciences, School of Veterinary Medicine, University of Wisconsin-Madison, Madison, Wisconsin, USA.
Li L
University of Chicagogrid.170205.1 Department of Medicine, Section of Rheumatology, Chicago, Illinois, USA.
Stamper CT
University of Chicagogrid.170205.1 Department of Medicine, Section of Rheumatology, Chicago, Illinois, USA. Committee on Immunology, University of Chicagogrid.170205.1, Chicago, Illinois, USA.
Dugan HL
University of Chicagogrid.170205.1 Department of Medicine, Section of Rheumatology, Chicago, Illinois, USA. Committee on Immunology, University of Chicagogrid.170205.1, Chicago, Illinois, USA.
Accola M
UW Health Clinical Laboratories, University of Wisconsin Hospital and Clinics, Madison, Wisconsin, USA.
Rehrauer W
UW Health Clinical Laboratories, University of Wisconsin Hospital and Clinics, Madison, Wisconsin, USA. Department of Pathology and Laboratory Medicine, University of Wisconsin-Madison, Madison, Wisconsin, USA.
Zheng NY
University of Chicagogrid.170205.1 Department of Medicine, Section of Rheumatology, Chicago, Illinois, USA.
Huang M
University of Chicagogrid.170205.1 Department of Medicine, Section of Rheumatology, Chicago, Illinois, USA.
Wang J
University of Chicagogrid.170205.1 Department of Medicine, Section of Rheumatology, Chicago, Illinois, USA.
Erickson SA
University of Chicagogrid.170205.1 Department of Medicine, Section of Rheumatology, Chicago, Illinois, USA.
Utset HA
University of Chicagogrid.170205.1 Department of Medicine, Section of Rheumatology, Chicago, Illinois, USA.
Graves HM
University of Chicagogrid.170205.1 Department of Medicine, Section of Rheumatology, Chicago, Illinois, USA.
Amanat F
Department of Microbiology, Icahn School of Medicine at Mount Sinaigrid.59734.3c, New York, New York, USA.
Sather DN
Center for Global Infectious Disease Research, Seattle Children's Research Institute, Seattle, Washington, USA. Department of Pediatrics, University of Washington, Seattle, Washington, USA. Department of Global Health, University of Washington, Seattle, Washington, USA.
Krammer F
Department of Microbiology, Icahn School of Medicine at Mount Sinaigrid.59734.3c, New York, New York, USA.
Kawaoka Y
Influenza Research Institute, Department of Pathobiological Sciences, School of Veterinary Medicine, University of Wisconsin-Madison, Madison, Wisconsin, USA. Division of Virology, Department of Microbiology and Immunology, Institute of Medical Science, University of Tokyo, Tokyo, Japan.
Wilson PC
University of Chicagogrid.170205.1 Department of Medicine, Section of Rheumatology, Chicago, Illinois, USA. Committee on Immunology, University of Chicagogrid.170205.1, Chicago, Illinois, USA.

MeSH

AdultAntibodies, MonoclonalAntibodies, ViralBroadly Neutralizing AntibodiesCOVID-19ConvalescenceEpitopesFemaleHumansMaleMiddle AgedNeutralization TestsPandemicsPlasmaProtein BindingSARS-CoV-2Spike Glycoprotein, Coronavirus

Pub Type(s)

Clinical Trial, Phase I
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

34781736

Citation

Changrob, Siriruk, et al. "Cross-Neutralization of Emerging SARS-CoV-2 Variants of Concern By Antibodies Targeting Distinct Epitopes On Spike." MBio, vol. 12, no. 6, 2021, pp. e0297521.
Changrob S, Fu Y, Guthmiller JJ, et al. Cross-Neutralization of Emerging SARS-CoV-2 Variants of Concern by Antibodies Targeting Distinct Epitopes on Spike. mBio. 2021;12(6):e0297521.
Changrob, S., Fu, Y., Guthmiller, J. J., Halfmann, P. J., Li, L., Stamper, C. T., Dugan, H. L., Accola, M., Rehrauer, W., Zheng, N. Y., Huang, M., Wang, J., Erickson, S. A., Utset, H. A., Graves, H. M., Amanat, F., Sather, D. N., Krammer, F., Kawaoka, Y., & Wilson, P. C. (2021). Cross-Neutralization of Emerging SARS-CoV-2 Variants of Concern by Antibodies Targeting Distinct Epitopes on Spike. MBio, 12(6), e0297521. https://doi.org/10.1128/mBio.02975-21
Changrob S, et al. Cross-Neutralization of Emerging SARS-CoV-2 Variants of Concern By Antibodies Targeting Distinct Epitopes On Spike. mBio. 2021 12 21;12(6):e0297521. PubMed PMID: 34781736.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Cross-Neutralization of Emerging SARS-CoV-2 Variants of Concern by Antibodies Targeting Distinct Epitopes on Spike. AU - Changrob,Siriruk, AU - Fu,Yanbin, AU - Guthmiller,Jenna J, AU - Halfmann,Peter J, AU - Li,Lei, AU - Stamper,Christopher T, AU - Dugan,Haley L, AU - Accola,Molly, AU - Rehrauer,William, AU - Zheng,Nai-Ying, AU - Huang,Min, AU - Wang,Jiaolong, AU - Erickson,Steven A, AU - Utset,Henry A, AU - Graves,Hortencia M, AU - Amanat,Fatima, AU - Sather,D Noah, AU - Krammer,Florian, AU - Kawaoka,Yoshihiro, AU - Wilson,Patrick C, Y1 - 2021/11/16/ PY - 2021/11/17/pubmed PY - 2022/1/6/medline PY - 2021/11/16/entrez KW - SARS-CoV-2 KW - humoral immunity KW - immune memory KW - infectious disease KW - monoclonal antibodies KW - single cell KW - variants of concern SP - e0297521 EP - e0297521 JF - mBio JO - mBio VL - 12 IS - 6 N2 - Several severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants have arisen that exhibit increased viral transmissibility and partial evasion of immunity induced by natural infection and vaccination. To address the specific antibody targets that were affected by recent viral variants, we generated 43 monoclonal antibodies (mAbs) from 10 convalescent donors that bound three distinct domains of the SARS-CoV-2 spike. Viral variants harboring mutations at K417, E484, and N501 could escape most of the highly potent antibodies against the receptor binding domain (RBD). Despite this, we identified 12 neutralizing mAbs against three distinct regions of the spike protein that neutralize SARS-CoV-2 and variants of concern (VOCs), including B.1.1.7 (alpha), P.1 (gamma), and B.1.617.2 (delta). Notably, antibodies targeting distinct epitopes could neutralize discrete variants, suggesting that different variants may have evolved to disrupt the binding of particular neutralizing antibody classes. These results underscore that humans exposed to the first pandemic wave of prototype SARS-CoV-2 possess neutralizing antibodies against current variants and that it is critical to induce antibodies targeting multiple distinct epitopes of the spike that can neutralize emerging variants of concern. IMPORTANCE We describe the binding and neutralization properties of a new set of human monoclonal antibodies derived from memory B cells of 10 coronavirus disease 2019 (COVID-19) convalescent donors in the first pandemic wave of prototype SARS-CoV-2. There were 12 antibodies targeting distinct epitopes on spike, including two sites on the RBD and one on the N-terminal domain (NTD), that displayed cross-neutralization of VOCs, for which distinct antibody targets could neutralize discrete variants. This work underlines that natural infection by SARS-CoV-2 induces effective cross-neutralization against only some VOCs and supports the need for COVID-19 vaccination for robust induction of neutralizing antibodies targeting multiple epitopes of the spike protein to combat the current SARS-CoV-2 VOCs and any others that might emerge in the future. SN - 2150-7511 UR - https://www.unboundmedicine.com/medline/citation/34781736/Cross_Neutralization_of_Emerging_SARS_CoV_2_Variants_of_Concern_by_Antibodies_Targeting_Distinct_Epitopes_on_Spike_ DB - PRIME DP - Unbound Medicine ER -