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Conserved Neutralizing Epitopes on the N-Terminal Domain of Variant SARS-CoV-2 Spike Proteins

114 Pages Posted: 1 Feb 2022 Publication Status: Published

See all articles by Zijun Wang

Zijun Wang

Rockefeller University - Laboratory of Molecular Immunology

Frauke Muecksch

Rockefeller University - Laboratory of Retrovirology

Alice Cho

Rockefeller University - Laboratory of Molecular Immunology

Christian Gaebler

Rockefeller University - Laboratory of Molecular Immunology

Hans-Heinrich Hoffmann

Rockefeller University - Laboratory of Virology and Infectious Diseases

Victor Ramos

Rockefeller University - Laboratory of Molecular Immunology

Shuai Zong

Rockefeller University - Laboratory of Molecular Immunology

Melissa Cipolla

Rockefeller University - Laboratory of Molecular Immunology

Briana Johnson

Rockefeller University - Laboratory of Molecular Immunology

Fabian Schmidt

Rockefeller University - Laboratory of Retrovirology

Justin DaSilva

Rockefeller University - Laboratory of Retrovirology

Eva Bednarski

Rockefeller University - Laboratory of Retrovirology

Tarek Ben Tanfous

Rockefeller University - Laboratory of Molecular Immunology

Raphael Raspe

Rockefeller University - Laboratory of Molecular Immunology

Kaihui Yao

Rockefeller University - Laboratory of Molecular Immunology

Yu Lee

Stanford University - Department of Biology

Teresia Chen

Stanford University - Department of Biology

Martina Turroja

Rockefeller University - Laboratory of Molecular Immunology

Katrina G. Milard

Rockefeller University - Laboratory of Molecular Immunology

Juan Dizon

Rockefeller University - Laboratory of Molecular Immunology

Anna Kaczynska

Rockefeller University - Laboratory of Molecular Immunology

Anna Gazumyan

Rockefeller University - Laboratory of Molecular Immunology

Thiago Y. Oliveira

Rockefeller University - Laboratory of Molecular Immunology

Charles M. Rice

Rockefeller University - Laboratory of Virology and Infectious Diseases

Marina Caskey

Rockefeller University - Laboratory of Molecular Immunology

Paul Bieniasz

Rockefeller University - Laboratory of Retrovirology

Theodora Hatziioannou

Rockefeller University - Laboratory of Retrovirology

Christopher O. Barnes

Stanford University - Department of Biology

Michel Nussenzweig

Rockefeller University - Laboratory of Molecular Immunology

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Abstract

SARS-CoV-2 infection or vaccination produces neutralizing antibody responses that contribute to better clinical outcomes. The receptor binding domain (RBD) and the N-terminal domain (NTD) of the spike trimer (S) constitute the two major neutralizing targets for the antibody system. Neutralizing antibodies targeting the RBD bind to several different sites on this domain. In contrast, most neutralizing antibodies to NTD characterized to date bind to a single supersite, however these antibodies were obtained by methods that were not NTD specific. Here we use NTD specific probes to focus on anti-NTD memory B cells in a cohort of pre-omicron infected individuals some of which were also vaccinated. Of 275 NTD binding antibodies tested 103 neutralized at least one of three tested strains: Wuhan- H u-1, Gamma, or PMS20, a synthetic variant which is extensively mutated in the NTD supersite. Among the 43 neutralizing antibodies that were further characterized, we found 6 complementation groups based on competition binding experiments. 58% targeted epitopes outside the NTD supersite, and 58% neutralized either Gamma or Omicron, but only 14% were broad neutralizers. Three of the broad neutralizers were characterized structurally. C1520 and C1791 recognize epitopes on opposite faces of the NTD with a distinct binding pose relative to previously described antibodies allowing for greater potency and cross-reactivity with 7 different variants including Beta, Delta, Gamma and Omicron. Antibody C1717 represents a previously uncharacterized class of NTD-directed antibodies that recognizes the viral membrane proximal side of the NTD and SD2 domain, leading to cross-neutralization of Beta, Gamma and Omicron. We conclude SARS-CoV-2 infection and/or Wuhan-Hu-1 mRNA vaccination produces a diverse collection of memory B cells that produce anti-NTD antibodies some of which can neutralize variants of concern. Rapid recruitment of these cells into the antibody secreting plasma cell compartment upon re-infection likely contributes to the relatively benign course of subsequent infections with SARS-CoV-2 variants including omicron.

Funding: This work was supported by NIH grant P01-AI138398-S1 (M.C.N.) and 2U19AI111825 (M.C.N.). R37-AI64003 to P.D.B.; R01AI78788 to T.H.; C.O.B. is supported by the Howard Hughes Medical Institute Hanna Gray Fellowship and is a Chan Zuckerberg Biohub investigator. C.G. was supported by the Robert S. Wennett Post-Doctoral Fellowship and the Shapiro-Silverberg Fund for the Advancement of Translational Research. C.G. and Z.W. were supported in part by the National Center for Advancing Translational Sciences (National Institutes of Health Clinical and Translational Science Award program, grant UL1 TR001866). P.D.B. and M.C.N. are Howard Hughes Medical Institute Investigators.

Declaration of Interests: All authors declare no conflict of interest.

Ethics Approval Statement: Samples were obtained from 62 individuals under a study protocol approved by the Rockefeller University in New York from April 1, 2020 to March 26, 2021 as described in (Robbiani et al., 2020; Wang et al., 2021c). All participants provided written informed consent before participation in the study, and the study was conducted in accordance with Good Clinical Practice.

Suggested Citation

Wang, Zijun and Muecksch, Frauke and Cho, Alice and Gaebler, Christian and Hoffmann, Hans-Heinrich and Ramos, Victor and Zong, Shuai and Cipolla, Melissa and Johnson, Briana and Schmidt, Fabian and DaSilva, Justin and Bednarski, Eva and Ben Tanfous, Tarek and Raspe, Raphael and Yao, Kaihui and Lee, Yu and Chen, Teresia and Turroja, Martina and Milard, Katrina G. and Dizon, Juan and Kaczynska, Anna and Gazumyan, Anna and Oliveira, Thiago Y. and Rice, Charles M. and Caskey, Marina and Bieniasz, Paul and Hatziioannou, Theodora and Barnes, Christopher O. and Nussenzweig, Michel, Conserved Neutralizing Epitopes on the N-Terminal Domain of Variant SARS-CoV-2 Spike Proteins. Available at SSRN: https://ssrn.com/abstract=4023678 or http://dx.doi.org/10.2139/ssrn.4023678
This version of the paper has not been formally peer reviewed.

Zijun Wang

Rockefeller University - Laboratory of Molecular Immunology ( email )

New York, NY 10065
United States

Frauke Muecksch

Rockefeller University - Laboratory of Retrovirology ( email )

New York, NY
United States

Alice Cho

Rockefeller University - Laboratory of Molecular Immunology ( email )

New York, NY 10065
United States

Christian Gaebler

Rockefeller University - Laboratory of Molecular Immunology ( email )

New York, NY 10065
United States

Hans-Heinrich Hoffmann

Rockefeller University - Laboratory of Virology and Infectious Diseases ( email )

United States

Victor Ramos

Rockefeller University - Laboratory of Molecular Immunology ( email )

New York, NY 10065
United States

Shuai Zong

Rockefeller University - Laboratory of Molecular Immunology ( email )

New York, NY 10065
United States

Melissa Cipolla

Rockefeller University - Laboratory of Molecular Immunology ( email )

New York, NY 10065
United States

Briana Johnson

Rockefeller University - Laboratory of Molecular Immunology ( email )

New York, NY 10065
United States

Fabian Schmidt

Rockefeller University - Laboratory of Retrovirology ( email )

New York, NY
United States

Justin DaSilva

Rockefeller University - Laboratory of Retrovirology ( email )

New York, NY
United States

Eva Bednarski

Rockefeller University - Laboratory of Retrovirology ( email )

New York, NY
United States

Tarek Ben Tanfous

Rockefeller University - Laboratory of Molecular Immunology ( email )

New York, NY 10065
United States

Raphael Raspe

Rockefeller University - Laboratory of Molecular Immunology ( email )

New York, NY 10065
United States

Kaihui Yao

Rockefeller University - Laboratory of Molecular Immunology ( email )

New York, NY 10065
United States

Yu Lee

Stanford University - Department of Biology ( email )

Gilbert Building, Rm 109
371 Serra Mall
Stanford, CA 94305
United States

Teresia Chen

Stanford University - Department of Biology ( email )

Gilbert Building, Rm 109
371 Serra Mall
Stanford, CA 94305
United States

Martina Turroja

Rockefeller University - Laboratory of Molecular Immunology ( email )

New York, NY 10065
United States

Katrina G. Milard

Rockefeller University - Laboratory of Molecular Immunology ( email )

New York, NY 10065
United States

Juan Dizon

Rockefeller University - Laboratory of Molecular Immunology ( email )

New York, NY 10065
United States

Anna Kaczynska

Rockefeller University - Laboratory of Molecular Immunology ( email )

New York, NY 10065
United States

Anna Gazumyan

Rockefeller University - Laboratory of Molecular Immunology ( email )

New York, NY 10065
United States

Thiago Y. Oliveira

Rockefeller University - Laboratory of Molecular Immunology ( email )

New York, NY 10065
United States

Charles M. Rice

Rockefeller University - Laboratory of Virology and Infectious Diseases ( email )

United States

Marina Caskey

Rockefeller University - Laboratory of Molecular Immunology ( email )

New York, NY 10065
United States

Paul Bieniasz

Rockefeller University - Laboratory of Retrovirology ( email )

New York, NY
United States

Theodora Hatziioannou

Rockefeller University - Laboratory of Retrovirology ( email )

New York, NY
United States

Christopher O. Barnes

Stanford University - Department of Biology ( email )

Gilbert Building, Rm 109
371 Serra Mall
Stanford, CA 94305
United States

Michel Nussenzweig (Contact Author)

Rockefeller University - Laboratory of Molecular Immunology ( email )

New York, NY 10065
United States

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