Convergence of immune escape strategies highlights plasticity of SARS-CoV-2 spike

  1. Xiaodi Yu
  2. Jarek Juraszek
  3. Lucy Rutten
  4. Mark J. G. Bakkers
  5. Sven Blokland
  6. Jelle M. Melchers
  7. Niels J. F. van den Broek
  8. Annemiek Y. W. Verwilligen
  9. Pravien Abeywickrema
  10. Johan Vingerhoets
  11. Jean-Marc Neefs
  12. Shah A. Mohamed Bakhash
  13. Pavitra Roychoudhury
  14. Alex Greninger
  15. Sujata Sharma
  16. Johannes P. M. Langedijk

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Abstract

The global spread of the SARS-CoV-2 virus has resulted in emergence of lineages which impact the effectiveness of immunotherapies and vaccines that are based on the early Wuhan isolate. All currently approved vaccines employ the spike protein S, as it is the target for neutralizing antibodies. Here we describe two SARS-CoV-2 isolates with unusually large deletions in the N-terminal domain (NTD) of the spike. Cryo-EM structural analysis shows that the deletions result in complete reshaping of the NTD supersite, an antigenically important region of the NTD. For both spike variants the remodeling of the NTD negatively affects binding of all tested NTD-specific antibodies in and outside of the NTD supersite. For one of the variants, we observed a P9L mediated shift of the signal peptide cleavage site resulting in the loss of a disulfide-bridge; a unique escape mechanism with high antigenic impact. Although the observed deletions and disulfide mutations are rare, similar modifications have become independently established in several other lineages, indicating a possibility to become more dominant in the future. The observed plasticity of the NTD foreshadows its broad potential for immune escape with the continued spread of SARS-CoV-2.

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  1. Version published to 10.1371/journal.ppat.1011308
  2. ScreenIT

    SciScore for 10.1101/2022.03.31.486561: (What is this?)

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

    Table 1: Rigor

    NIH rigor criteria are not applicable to paper type.

    Table 2: Resources

    Antibodies
    SentencesResources
    For 2-51, DH1055, 4A8, S1M11, S2E12, C144, 2-43 and S309 the heavy and light chain were cloned into a single IgG1 expression vector to express a fully human IgG1 antibody.
    C144
    suggested: (Leinco Technologies Cat# C144, RRID:AB_2828501)
    human IgG1
    suggested: None
    BioLayer Interferometry (BLI): The antibodies were immobilized on anti-hIgG (AHC) sensors (FortéBio cat#18-5060) in 1x kinetics buffer (FortéBio cat#18-1092) in 96-well black flat bottom polypylene microplates (FortéBio cat#3694).
    anti-hIgG (AHC
    suggested: None
    Experimental Models: Cell Lines
    SentencesResources
    HEK293 cells were transfected with full-length S, human ACE2, human TMPRSS2 and GFP.
    HEK293
    suggested: CLS Cat# 300192/p777_HEK293, RRID:CVCL_0045)
    Recombinant DNA
    SentencesResources
    All proteins were expressed from pcDNA2004 plasmids using Trans-IT transfection reagent according to the manufacturer’s instructions.
    pcDNA2004
    suggested: None
    Software and Algorithms
    SentencesResources
    The primer pairs used in SNAP were designed for generating libraries from first- or second-strand cDNA produced from viral isolates or clinical specimens enabling successful SARS-CoV-2 library preparation from samples with low viral titers.
    SNAP
    suggested: (SNAP, RRID:SCR_007936)
    The Swift Biosciences SARS-CoV2 Version 2.0 kit (Catalog # CovG1 V2-96) has been optimized to achieve additional genome coverage on the Illumina sequencing platforms.
    Swift Biosciences
    suggested: None
    Cryo-EM image processing: Dose-fractioned movies were gain-corrected, and beam-induced motion correction using MotionCor2(37) with the dose-weighting option.
    MotionCor2
    suggested: (MotionCor2, RRID:SCR_016499)
    The Spike particles were automatically picked from the dose-weighted, motion corrected average images using Relion 3.0(38).
    Relion
    suggested: (RELION, RRID:SCR_016274)
    The geometry parameters of the final models were validated in COOT and using MolProbity(45)and EMRinger(46).
    COOT
    suggested: (Coot, RRID:SCR_014222)
    Figures were produced using PyMOL (The PyMOL Molecular Graphics System) and Chimera.
    PyMOL
    suggested: (PyMOL, RRID:SCR_000305)
    When purified proteins were analyzed using SEC-MALS, μMALS detectors were inline and data was analyzed using Astra 7.3 software package.
    Astra
    suggested: (ASTRA, RRID:SCR_016255)

    Results from OddPub: We did not detect open data. We also did not detect open code. Researchers are encouraged to share open data when possible (see Nature blog).

    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: We found the following clinical trial numbers in your paper:

    IdentifierStatusTitle
    NCT04505722Active, not recruitingA Study of Ad26.COV2.S for the Prevention of SARS-CoV-2-Medi…

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

    Results from JetFighter: We did not find any issues relating to colormaps.

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

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

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  3. Version published to 10.1101/2022.03.31.486561v1 on bioRxiv