Structural basis of Omicron neutralization by affinity-matured public antibodies

  1. Daniel J. Sheward
  2. Pradeepa Pushparaj
  3. Hrishikesh Das
  4. Changil Kim
  5. Sungyong Kim
  6. Leo Hanke
  7. Robert Dyrdak
  8. Gerald McInerney
  9. Jan Albert
  10. Ben Murrell
  11. Gunilla B. Karlsson Hedestam
  12. B. Martin Hällberg

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Abstract

The SARS-CoV-2 Omicron 1 Variant of Concern (B.1.1.529) has spread rapidly in many countries. With a spike that is highly diverged from that of the pandemic founder, it escapes most available monoclonal antibody therapeutics 2,3 and erodes vaccine protection 4 . A public class of IGHV3-53-using SARS-CoV-2 neutralizing antibodies 5,6 typically fails to neutralize variants carrying mutations in the receptor-binding motif 7–11 , including Omicron. As antibodies from this class are likely elicited in most people following SARS-CoV-2 infection or vaccination, their subsequent affinity maturation is of particular interest. Here, we isolated IGHV3-53-using antibodies from an individual seven months after infection and identified several antibodies capable of broad and potent SARS-CoV-2 neutralization, extending to Omicron without loss of potency. By introducing select somatic hypermutations into a germline-reverted form of one such antibody, CAB-A17, we demonstrate the potential for commonly elicited antibodies to develop broad cross-neutralization through affinity maturation. Further, we resolved the structure of CAB-A17 Fab in complex with Omicron spike at an overall resolution of 2.6 Å by cryo-electron microscopy and defined the structural basis for this breadth. Thus, public SARS-CoV-2 neutralizing antibodies can, without modified spike vaccines, mature to cross-neutralize exceptionally antigenically diverged SARS-CoV-2 variants.

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  1. ScreenIT

    SciScore for 10.1101/2022.01.03.474825: (What is this?)

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

    Table 1: Rigor

    EthicsConsent: Informed consent was obtained from all participants as part of ethics approvals (Decisions# 2020-01620, 2020-02881 and 2020-05630) from the National Ethical Review Agency of Sweden.
    Sex as a biological variablenot detected.
    Randomizationnot detected.
    Blindingnot detected.
    Power Analysisnot detected.
    Cell Line Authenticationnot detected.

    Table 2: Resources

    Experimental Models: Cell Lines
    SentencesResources
    Cell culture: HEK293T cells (ATCC CRL-3216) and HEK293T-ACE2 cells (stably expressing human ACE2) were cultured in Dulbecco’s Modified Eagle Medium (high glucose, with sodium pyruvate) supplemented with 10% fetal calf serum, 100 units/ml penicillin, and 100 μg/ml streptomycin.
    HEK293T
    suggested: None
    HEK293T-ACE2
    suggested: None
    Software and Algorithms
    SentencesResources
    Therefore, 3D-classification was performed within CryoSparc 3.31 without pose alignment using 20 classes with a mask around the two RBDs in up conformations and their bound Fabs.
    CryoSparc
    suggested: (cryoSPARC, RRID:SCR_016501)
    Structure figures and EM density-map figures were generated with UCSF ChimeraX40 and COOT, respectively.
    COOT
    suggested: (Coot, RRID:SCR_014222)
    l analysis: Neutralizing IC50 values were calculated in Prism v9 (GraphPad Software) by fitting a four-parameter logistic curve, to neutralization by serial 3-fold dilutions.
    Prism
    suggested: (PRISM, RRID:SCR_005375)
    GraphPad
    suggested: (GraphPad Prism, RRID:SCR_002798)

    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: 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: 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.
    • 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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  2. Version published to 10.1101/2022.01.03.474825v1 on bioRxiv