SARS-CoV-2 spike conformation determines plasma neutralizing activity elicited by a wide panel of human vaccines

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Abstract

Numerous safe and effective COVID-19 vaccines have been developed worldwide that utilize various delivery technologies and engineering strategies. We show here that vaccines containing prefusion-stabilizing S mutations elicit antibody responses in humans with enhanced recognition of S and the S ₁ subunit relative to postfusion S, as compared to vaccines lacking these mutations or natural infection. Prefusion S and S ₁ antibody binding titers positively and equivalently correlated with neutralizing activity and depletion of S ₁-directed antibodies completely abrogated plasma neutralizing activity. We show that neutralizing activity is almost entirely directed to the S ₁ subunit and that variant cross-neutralization is mediated solely by RBD-specific antibodies. Our data provide a quantitative framework for guiding future S engineering efforts to develop vaccines with higher resilience to the emergence of variants than current technologies.

Abstract

SARS-CoV-2 S1 accounts for all vaccine-elicited plasma neutralization and cross-neutralization is mediated by RBD-specific antibodies.

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Most cited references 132

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A pneumonia outbreak associated with a new coronavirus of probable bat origin

Peng Zhou, Xing-Lou Yang, Xian-Guang Wang … (2020)

Since the outbreak of severe acute respiratory syndrome (SARS) 18 years ago, a large number of SARS-related coronaviruses (SARSr-CoVs) have been discovered in their natural reservoir host, bats 1–4 . Previous studies have shown that some bat SARSr-CoVs have the potential to infect humans 5–7 . Here we report the identification and characterization of a new coronavirus (2019-nCoV), which caused an epidemic of acute respiratory syndrome in humans in Wuhan, China. The epidemic, which started on 12 December 2019, had caused 2,794 laboratory-confirmed infections including 80 deaths by 26 January 2020. Full-length genome sequences were obtained from five patients at an early stage of the outbreak. The sequences are almost identical and share 79.6% sequence identity to SARS-CoV. Furthermore, we show that 2019-nCoV is 96% identical at the whole-genome level to a bat coronavirus. Pairwise protein sequence analysis of seven conserved non-structural proteins domains show that this virus belongs to the species of SARSr-CoV. In addition, 2019-nCoV virus isolated from the bronchoalveolar lavage fluid of a critically ill patient could be neutralized by sera from several patients. Notably, we confirmed that 2019-nCoV uses the same cell entry receptor—angiotensin converting enzyme II (ACE2)—as SARS-CoV.

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SARS-CoV-2 Cell Entry Depends on ACE2 and TMPRSS2 and Is Blocked by a Clinically Proven Protease Inhibitor

Markus Hoffmann, Hannah Kleine-Weber, Simon Schroeder … (2020)

Summary The recent emergence of the novel, pathogenic SARS-coronavirus 2 (SARS-CoV-2) in China and its rapid national and international spread pose a global health emergency. Cell entry of coronaviruses depends on binding of the viral spike (S) proteins to cellular receptors and on S protein priming by host cell proteases. Unravelling which cellular factors are used by SARS-CoV-2 for entry might provide insights into viral transmission and reveal therapeutic targets. Here, we demonstrate that SARS-CoV-2 uses the SARS-CoV receptor ACE2 for entry and the serine protease TMPRSS2 for S protein priming. A TMPRSS2 inhibitor approved for clinical use blocked entry and might constitute a treatment option. Finally, we show that the sera from convalescent SARS patients cross-neutralized SARS-2-S-driven entry. Our results reveal important commonalities between SARS-CoV-2 and SARS-CoV infection and identify a potential target for antiviral intervention.

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UCSF Chimera--a visualization system for exploratory research and analysis.

Eric F. Pettersen, Thomas Goddard, Conrad Huang … (2004)

The design, implementation, and capabilities of an extensible visualization system, UCSF Chimera, are discussed. Chimera is segmented into a core that provides basic services and visualization, and extensions that provide most higher level functionality. This architecture ensures that the extension mechanism satisfies the demands of outside developers who wish to incorporate new features. Two unusual extensions are presented: Multiscale, which adds the ability to visualize large-scale molecular assemblies such as viral coats, and Collaboratory, which allows researchers to share a Chimera session interactively despite being at separate locales. Other extensions include Multalign Viewer, for showing multiple sequence alignments and associated structures; ViewDock, for screening docked ligand orientations; Movie, for replaying molecular dynamics trajectories; and Volume Viewer, for display and analysis of volumetric data. A discussion of the usage of Chimera in real-world situations is given, along with anticipated future directions. Chimera includes full user documentation, is free to academic and nonprofit users, and is available for Microsoft Windows, Linux, Apple Mac OS X, SGI IRIX, and HP Tru64 Unix from http://www.cgl.ucsf.edu/chimera/. Copyright 2004 Wiley Periodicals, Inc.

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Author and article information

Contributors

John E. Bowen:

ORCID: https://orcid.org/0000-0003-3590-9727

Role: ConceptualizationRole: Formal analysisRole: InvestigationRole: MethodologyRole: Project administrationRole: SupervisionRole: ValidationRole: VisualizationRole: Writing - original draftRole: Writing - review & editing

Cameron Stewart:

ORCID: https://orcid.org/0000-0002-2786-6256

Role: InvestigationRole: ResourcesRole: Validation

Alexandra C. Walls:

ORCID: https://orcid.org/0000-0002-9636-8330

Role: ConceptualizationRole: MethodologyRole: SupervisionRole: Writing - review & editing

Anshu Joshi: Role: Data curationRole: Formal analysisRole: InvestigationRole: MethodologyRole: ValidationRole: Visualization

Kaitlin R. Sprouse:

ORCID: https://orcid.org/0000-0003-0007-2226

Role: ConceptualizationRole: Formal analysisRole: InvestigationRole: ResourcesRole: ValidationRole: Visualization

Nicholas M. Franko:

ORCID: https://orcid.org/0000-0001-8165-6332

Role: Data curationRole: ResourcesRole: Writing - original draft

Jennifer K. Logue:

ORCID: https://orcid.org/0000-0002-7889-8960

Role: InvestigationRole: MethodologyRole: ResourcesRole: Writing - review & editing

Ignacio G. Mazzitelli:

ORCID: https://orcid.org/0000-0001-9351-5799

Role: Resources

Kumail Ahmed:

ORCID: https://orcid.org/0000-0002-6457-4869

Role: Data curationRole: Formal analysisRole: InvestigationRole: MethodologyRole: Project administrationRole: ResourcesRole: ValidationRole: Visualization

Gyorgy Snell:

ORCID: https://orcid.org/0000-0003-1475-659X

Role: Resources

Najeeha Talat Iqbal:

ORCID: https://orcid.org/0000-0003-4026-5655

Role: InvestigationRole: Resources

Jorge Geffner:

ORCID: https://orcid.org/0000-0002-4750-9686

Role: InvestigationRole: MethodologyRole: Resources

Alessandra Bandera:

ORCID: https://orcid.org/0000-0001-9440-4601

Role: InvestigationRole: ResourcesRole: VisualizationRole: Writing - review & editing

Andrea Gori:

ORCID: https://orcid.org/0000-0001-6587-4794

Role: InvestigationRole: Project administrationRole: SupervisionRole: VisualizationRole: Writing - review & editing

Wesley C. Van Voorhis:

ORCID: https://orcid.org/0000-0001-6141-2015

Role: MethodologyRole: ResourcesRole: SupervisionRole: ValidationRole: Writing - review & editing

Renata Grifantini:

ORCID: https://orcid.org/0000-0003-0024-3355

Role: MethodologyRole: ResourcesRole: Writing - review & editing

Helen Y. Chu:

ORCID: https://orcid.org/0000-0001-8502-9600

Role: ConceptualizationRole: Data curationRole: Funding acquisitionRole: InvestigationRole: Project administrationRole: ResourcesRole: Supervision

Davide Corti:

ORCID: https://orcid.org/0000-0002-5797-1364

Role: ConceptualizationRole: ResourcesRole: Writing - review & editing

David Veesler:

ORCID: https://orcid.org/0000-0002-6019-8675

Role: ConceptualizationRole: Formal analysisRole: Funding acquisitionRole: Project administrationRole: ResourcesRole: SupervisionRole: ValidationRole: VisualizationRole: Writing - original draft

Journal

Journal ID (nlm-ta): Sci Immunol

Journal ID (iso-abbrev): Sci Immunol

Journal ID (publisher-id): sciimmunol

Journal ID (hwp): immunology

Title: Science Immunology

Publisher: American Association for the Advancement of Science

ISSN (Electronic): 2470-9468

Publication date (Electronic, pub): 10 November 2022

Publication date PMC-release: 10 November 2022

Electronic Location Identifier: eadf1421

Affiliations

[ ¹ ]Department of Biochemistry, University of Washington, Seattle, WA 98195, USA.

[ ² ]Howard Hughes Medical Institute, University of Washington, Seattle, WA 98195, USA.

[ ³ ]Division of Allergy and Infectious Diseases, University of Washington, Seattle, WA 98195, USA.

[ ⁴ ]Instituto de Investigaciones Biomédicas en Retrovirus y SIDA (INBIRS), Facultad de Medicina, Buenos Aires C1121ABG, Argentina.

[ ⁵ ]McKetta Department of Chemical Engineering, The University of Texas at Austin, Austin, TX.

[ ⁶ ]Institute for Research in Biomedicine, Università della Svizzera Italiana, 6500 Bellinzona, Switzerland.

[ ⁷ ]Center for Emerging and Re-emerging Infectious Diseases, Division of Allergy and Infectious Diseases, Department of Medicine, University of Washington School of Medicine, Seattle, WA 98195, USA.

[ ⁸ ]Department of Paediatrics and Child Health, and Biological & Biomedical Sciences, Aga Khan University, Karachi 74800, Pakistan.

[ ⁹ ]Center for Infectious Disease and Vaccine Research, La Jolla Institute for Immunology, La Jolla, CA 92037, USA.

[ ¹⁰ ]Department of Medicine, Division of Infectious Diseases and Global Public Health, University of California, San Diego, La Jolla, CA UC92037, USA.

[ ¹¹ ]Vir Biotechnology, San Francisco, CA 94158, USA.

[ ¹² ]Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Center, Seattle, WA, USA.

[ ¹³ ]Infectious Diseases Unit, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, 20122 Milan, Italy.

[ ¹⁴ ]Department of Chemistry, Stony Brook University, Stony Brook, New York 11794, United States.

[ ¹⁵ ]Laufer Center for Physical and Quantitative Biology, Stony Brook University, Stony Brook, New York 11794, United States.

[ ¹⁶ ]INGM, Istituto Nazionale Genetica Molecolare “Romeo ed Enrica Invernizzi”, 20122 Milan, Italy.

[ ¹⁷ ]Humabs Biomed SA, a subsidiary of Vir Biotechnology, 6500 Bellinzona, Switzerland.

Author notes

[* ]Corresponding author. Email: dveesler@ 123456uw.edu

Author information

John E. Bowen https://orcid.org/0000-0003-3590-9727

Cameron Stewart https://orcid.org/0000-0002-2786-6256

Alexandra C. Walls https://orcid.org/0000-0002-9636-8330

Kaitlin R. Sprouse https://orcid.org/0000-0003-0007-2226

M. Alejandra Tortorici https://orcid.org/0000-0002-2260-2577

Nicholas M. Franko https://orcid.org/0000-0001-8165-6332

Jennifer K. Logue https://orcid.org/0000-0002-7889-8960

Ignacio G. Mazzitelli https://orcid.org/0000-0001-9351-5799

Sasha W Tiles https://orcid.org/0000-0002-6877-1341

Kumail Ahmed https://orcid.org/0000-0002-6457-4869

Asefa Shariq https://orcid.org/0000-0003-1706-9461

Gyorgy Snell https://orcid.org/0000-0003-1475-659X

Najeeha Talat Iqbal https://orcid.org/0000-0003-4026-5655

Jorge Geffner https://orcid.org/0000-0002-4750-9686

Alessandra Bandera https://orcid.org/0000-0001-9440-4601

Andrea Gori https://orcid.org/0000-0001-6587-4794

Wesley C. Van Voorhis https://orcid.org/0000-0001-6141-2015

Renata Grifantini https://orcid.org/0000-0003-0024-3355

Helen Y. Chu https://orcid.org/0000-0001-8502-9600

Davide Corti https://orcid.org/0000-0002-5797-1364

David Veesler https://orcid.org/0000-0002-6019-8675

Article

Publisher ID: adf1421

DOI: 10.1126/sciimmunol.adf1421

PMC ID: 9765460

PubMed ID: 36356052

SO-VID: fbf1c9bd-92d8-4ede-bf27-48a999d8f27f

Copyright © Copyright © 2022 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution License 4.0 (CC BY).

License:

This is an open-access article distributed under the terms of the Creative Commons Attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

History

Date received : 01 October 2022

Date accepted : 07 November 2022

Funding

Funded by: FundRef http://dx.doi.org/10.13039/100000057, National Institute of General Medical Sciences;

Award ID: R01GM120553

Funded by: FundRef http://dx.doi.org/10.13039/100000060, National Institute of Allergy and Infectious Diseases;

Award ID: DP1AI158186

Funded by: FundRef http://dx.doi.org/10.13039/100000060, National Institute of Allergy and Infectious Diseases;

Award ID: HHSN272201700059C

Funded by: FundRef http://dx.doi.org/10.13039/100000060, National Institute of Allergy and Infectious Diseases;

Award ID: U01 AI151698

Funded by: FundRef http://dx.doi.org/10.13039/100010269, Wellcome;

Award ID: OPP1156262

Funded by: FundRef http://dx.doi.org/10.13039/501100013854, Alzheimer Nadační Fond;

Funded by: National Institute of Health;

Award ID: S10OD032290

Funded by: National Institute of Health;

Award ID: U01 AI151698

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SARS-CoV-2 spike conformation determines plasma neutralizing activity elicited by a wide panel of human vaccines

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Novel Coronavirus Disease COVID-19

Most cited references 132

A pneumonia outbreak associated with a new coronavirus of probable bat origin

SARS-CoV-2 Cell Entry Depends on ACE2 and TMPRSS2 and Is Blocked by a Clinically Proven Protease Inhibitor

UCSF Chimera--a visualization system for exploratory research and analysis.

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Cited by 22

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