SARS-CoV-2 Beta variant infection elicits potent lineage-specific and cross-reactive antibodies

  1. S. Momsen Reincke
  2. Meng Yuan
  3. Hans-Christian Kornau
  4. Victor M. Corman
  5. Scott van Hoof
  6. Elisa Sánchez-Sendin
  7. Melanie Ramberger
  8. Wenli Yu
  9. Yuanzi Hua
  10. Henry Tien
  11. Marie Luisa Schmidt
  12. Tatjana Schwarz
  13. Lara Maria Jeworowski
  14. Sarah E. Brandl
  15. Helle Foverskov Rasmussen
  16. Marie A. Homeyer
  17. Laura Stöffler
  18. Martin Barner
  19. Désirée Kunkel
  20. Shufan Huo
  21. Johannes Horler
  22. Niels von Wardenburg
  23. Inge Kroidl
  24. Tabea M. Eser
  25. Andreas Wieser
  26. Christof Geldmacher
  27. Michael Hoelscher
  28. Hannes Gänzer
  29. Günter Weiss
  30. Dietmar Schmitz
  31. Christian Drosten
  32. Harald Prüss
  33. Ian A. Wilson
  34. Jakob Kreye

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Abstract

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Beta variant of concern (VOC) resists neutralization by major classes of antibodies from COVID-19 patients and vaccinated individuals. In this study, serum of Beta-infected patients revealed reduced cross-neutralization of wild-type virus. From these patients, we isolated Beta-specific and cross-reactive receptor-binding domain (RBD) antibodies. The Beta-specificity results from recruitment of VOC-specific clonotypes and accommodation of mutations present in Beta and Omicron into a major antibody class that is normally sensitive to these mutations. The Beta-elicited cross-reactive antibodies share genetic and structural features with wild type–elicited antibodies, including a public VH1-58 clonotype that targets the RBD ridge. These findings advance our understanding of the antibody response to SARS-CoV-2 shaped by antigenic drift, with implications for design of next-generation vaccines and therapeutics.

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  1. Version published to 10.1126/science.abm5835
  2. ScreenIT

    SciScore for 10.1101/2021.09.30.462420: (What is this?)

    Please note, not all rigor criteria are appropriate for all manuscripts.

    Table 1: Rigor

    EthicsConsent: Patient recruitment: All donors have given written informed consent and analyses were approved by the Institutional Review Board of Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität Berlin, and Berlin Institute of Health, Berlin (study protocol number EA1/258/18), the Institutional Review Board of the Faculty of Medicine at Ludwig-Maximilians-Universität (LMU) Munich, Germany (20-371), as well as the ethics committee of the Innsbruck Medical University (1167/2020).
    IRB: Patient recruitment: All donors have given written informed consent and analyses were approved by the Institutional Review Board of Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität Berlin, and Berlin Institute of Health, Berlin (study protocol number EA1/258/18), the Institutional Review Board of the Faculty of Medicine at Ludwig-Maximilians-Universität (LMU) Munich, Germany (20-371), as well as the ethics committee of the Innsbruck Medical University (1167/2020).
    Sex as a biological variablenot detected.
    Randomizationnot detected.
    Blindingnot detected.
    Power Analysisnot detected.
    Cell Line Authenticationnot detected.

    Table 2: Resources

    Antibodies
    SentencesResources
    Diagnostic antibody testing: Initial serological testing of patient samples was performed using a solid phase immunoassay (SeraSpot®Anti-SARS-CoV-2 IgG, Seramun Diagnostica GmbH, Heidesee, Germany).
    SeraSpot®Anti-SARS-CoV-2 IgG
    suggested: None
    After washing, bound antibodies were detected by incubation with horseradish peroxidase (HRP)-labeled anti-human IgG for 30 minutes at room temperature.
    anti-human IgG
    suggested: None
    Second, the presence of SARS-CoV-2 S1-specific antibodies was analyzed using a commercially available anti-SARS-CoV-2-S1 IgG ELISA (EUROIMMUN Medizinische Labordiagnostika AG, Lübeck, Germany) according to the manufacturer’s instructions.
    anti-SARS-CoV-2-S1 IgG
    suggested: None
    After His-tagged RBD Beta was immobilized on anti-Penta His BLI sensors, sensors were first dipped into CS82 IgG (50 μg/ml), and then dipped into indicated IgG antibodies (12.5 μg/ml).
    anti-Penta
    suggested: (Bio-Rad Cat# MCA5995P, RRID:AB_2888689)
    Experimental Models: Cell Lines
    SentencesResources
    His-tagged recombinant RBD Beta protein was produced in HEK cells (ACROBiosystems, SPD-C52Hp) and covalently labeled using CruzFluor488 (Santa Cruz Biotechnology, sc-362617) according to the manufacturer’s instructions.
    HEK
    suggested: None
    Briefly, HEK293T cell-secreted RBD-Fc fusion proteins composed of the RBD-SD1 component of the SARS-CoV-2 spike S1 subunit (amino acids 319-591) and the constant region of rabbit IgG1 heavy chain (Fc) were immobilized onto 96-well plates via anti-rabbit IgG (Dianova, 711-005-152)
    HEK293T
    suggested: None
    In brief, Vero E6 cells (1.6 x105 cells/well) were seeded in 24-well plates and incubated overnight.
    Vero E6
    suggested: None
    Recombinant DNA
    SentencesResources
    Crystallization and structural determination: The RBD (residues 333-529) of the SARS-CoV-2 spike (S) protein (GenBank: QHD43416.1) and the Beta variant that carries three mutations on the RBD (K417N, E484K, and N501Y) were cloned into a customized pFastBac vector (37), and fused with an N-terminal gp67 signal peptide and C-terminal His6 tag.
    pFastBac
    suggested: RRID:Addgene_1925)
    For expression and purification of the Fabs, heavy and light chains were cloned into phCMV3.
    phCMV3
    suggested: None
    Software and Algorithms
    SentencesResources
    Cloning was considered successful when sequence identity was >99.5% as verified by the cBASE module of BASE software.
    BASE
    suggested: (BASE, RRID:SCR_010937)
    After identification of public clonotypes, they were plotted in a Circos plot using the R package circlize (33).
    Circos
    suggested: (Circos, RRID:SCR_011798)
    As the CoV-AbDab includes SARS-CoV-2 mAbs from other sources than humans, and against other epitopes than the RBD, the following selection criteria were used (nomenclature like in CoV-AbDab): Binds to: SARS-CoV-2,
    SARS-CoV-2
    suggested: (BioLegend Cat# 946101, RRID:AB_2892515)
    Iterative model building and refinement were carried out in COOT (41) and PHENIX (42), respectively (table S4).
    COOT
    suggested: (Coot, RRID:SCR_014222)
    PHENIX
    suggested: (Phenix, RRID:SCR_014224)
    1 and all statistical analyses were performed using GraphPad Prism (9.2.0).
    GraphPad Prism
    suggested: (GraphPad Prism, RRID:SCR_002798)

    Results from OddPub: Thank you for sharing your data.

    Results from LimitationRecognizer: An explicit section about the limitations of the techniques employed in this study was not found. We encourage authors to address study limitations.

    Results from TrialIdentifier: No clinical trial numbers were referenced.

    Results from Barzooka: We did not find any issues relating to the usage of bar graphs.

    Results from JetFighter: Please consider improving the rainbow (“jet”) colormap(s) used on page 34. At least one figure is not accessible to readers with colorblindness and/or is not true to the data, i.e. not perceptually uniform.

    Results from rtransparent:
    • Thank you for including a conflict of interest statement. Authors are encouraged to include this statement when submitting to a journal.
    • Thank you for including a funding statement. Authors are encouraged to include this statement when submitting to a journal.
    • No protocol registration statement was detected.

    Results from scite Reference Check: We found no unreliable references.

    About SciScore

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  3. Version published to 10.1101/2021.09.30.462420v1 on bioRxiv