Immune escape of SARS-CoV-2 Omicron variant from mRNA vaccination-elicited RBD-specific memory B cells

  1. Aurélien Sokal
  2. Matteo Broketa
  3. Annalisa Meola
  4. Giovanna Barba-Spaeth
  5. Ignacio Fernández
  6. Slim Fourati
  7. Imane Azzaoui
  8. Andrea de La Selle
  9. Alexis Vandenberghe
  10. Anais Roeser
  11. Magali Bouvier-Alias
  12. Etienne Crickx
  13. Laetitia Languille
  14. Marc Michel
  15. Bertrand Godeau
  16. Sébastien Gallien
  17. Giovanna Melica
  18. Yann Nguyen
  19. Virginie Zarrouk
  20. Florence Canoui-Poitrine
  21. France Noizat-Pirenne
  22. Jérôme Megret
  23. Jean-Michel Pawlotsky
  24. Simon Fillatreau
  25. Etienne Simon-Lorière
  26. Jean-Claude Weill
  27. Claude-Agnès Reynaud
  28. Félix A. Rey
  29. Pierre Bruhns
  30. Pascal Chappert
  31. Matthieu Mahévas

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Abstract

Memory B cells (MBCs) represent a second layer of immune protection against SARS-CoV-2. Whether MBCs elicited by mRNA vaccines can recognize the Omicron variant is of major concern. We used bio-layer interferometry to assess the affinity against the receptor-binding-domain (RBD) of Omicron spike of 313 naturally expressed monoclonal IgG that were previously tested for affinity and neutralization against VOC prior to Omicron. We report here that Omicron evades recognition from a larger fraction of these antibodies than any of the previous VOCs. Additionally, whereas 30% of these antibodies retained high affinity against Omicron-RBD, our analysis suggest that Omicron specifically evades antibodies displaying potent neutralizing activity against the D614G and Beta variant viruses. Further studies are warranted to understand the consequences of a lower memory B cell potency on the overall protection associated with current vaccines.

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  1. ScreenIT

    SciScore for 10.1101/2021.12.21.473528: (What is this?)

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

    Table 1: Rigor

    Ethicsnot detected.
    Sex as a biological variablenot detected.
    Randomizationnot detected.
    Blindingnot detected.
    Power Analysisnot detected.
    Cell Line Authenticationnot detected.

    Table 2: Resources

    Antibodies
    SentencesResources
    anti-Human Fc Capture (AHC) biosensors (18-5060) were immersed in supernatants from single-cell memory B cell culture (or control monoclonal antibody) at 25°C for 1800 seconds.
    anti-Human Fc Capture ( AHC
    suggested: None
    All mAbs with ratio superior to two for these two combinations were labeled as binding both the N501 and K417 residues, as previously described for RBS-A type of anti-RBD mAbs (Yuan et al., 2021); 2/ mAbs affected by the B.1.351, P.1, B.1.617.1 and B.1.617.2 variants, but not the B.1.1.7 variant, were labeled as binding both the E484 and L452 residues based on reported data in the literature for RBS-B/C antibodies (Yuan et al., 2021; Starr et al., 2021).
    anti-RBD
    suggested: None
    RBS-B/C
    suggested: None
    Cells were fixed with 4% formaldehyde and foci were revealed using a rabbit anti-SARS-CoV-2 N antibody (gift of Nicolas Escriou) and anti-rabbit secondary HRP-conjugated secondary antibody.
    anti-SARS-CoV-2 N
    suggested: None
    anti-rabbit
    suggested: None
    Experimental Models: Cell Lines
    SentencesResources
    Vero E6 cells were seeded at 2×104 cells/well in a 96-well plate 24h before the assay.
    Vero E6
    suggested: None
    Recombinant DNA
    SentencesResources
    Recombinant protein purification: Construct design: The SARS-CoV-2 Receptor Binding Domain (RBD) was cloned in pcDNA3.1(+) encompassing the Spike (S) residues 331-528, and it was flanked by an N-terminal IgK signal peptide and a C-terminal Thrombin cleavage site followed by Hisx8, Strep and Avi tags.
    pcDNA3.1
    suggested: RRID:Addgene_79663)
    Software and Algorithms
    SentencesResources
    Sequence quality was verified with the CodonCode Aligner software (CodonCode Corporation)
    CodonCode Aligner
    suggested: None
    Computational analyses of VDJ sequences: Processed FASTA sequences from cultured single-cell VH sequencing were annotated using Igblast v1.16.0 against the human IMGT reference database.
    Igblast
    suggested: (IgBLAST, RRID:SCR_002873)
    VH repartition was calculated using the countGenes() function from the Immcantation/alakazam v1.1.0 R package.
    Immcantation/alakazam
    suggested: None
    3D representation of known mutations to the RBD surface: Panel D in Figure 5 was prepared with The PyMOL Molecular Graphics System, Version 2.1 Schrödinger, LLC.
    PyMOL
    suggested: (PyMOL, RRID:SCR_000305)
    Quantification and Statistical Analysis: Statistical analyses were all performed using GraphPad Prism 9.0 (La Jolla, CA, USA).
    GraphPad Prism
    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: We detected the following sentences addressing limitations in the study:
    A limitation to our conclusions relies in the fact that samples analyzed were collected early after the first vaccine boost in all individuals. The repertoire of COVID-19-naive vaccinated individuals has been shown to evolve up to 5 months after the boost (Cho et al., 2021; Goel et al., 2021a) and it remains to be assessed how this MBC repertoire will further evolve after an additional vaccine boost, with a third dose of the Wuhan (WT) spike mRNA vaccine currently being implemented in numerous countries. Additionally, our study was focused on the RBD domain of the SARS-CoV-2 spike protein, which represents the major target of neutralizing antibodies. However, neutralizing antibodies against other domains of the trimeric spike have been described, notably against the N-terminal domain (NTD) and these might be affected in a different way (Tong et al., 2021). A similar point could be made for memory T cell responses, which appear so far to be less affected by mutations selected by SARS-CoV-2 variants (Goel et al., 2021b). Answering these questions will provide us with crucial information regarding the available immune protection against Omicron or subsequent variants, and allow an informed decision as to whether vaccine specifically targeted against VOCs will need to be implemented in the near future.

    Results from TrialIdentifier: We found the following clinical trial numbers in your paper:

    IdentifierStatusTitle
    NCT04402892Not yet recruitingCOVID-19: SARS-CoV-2 Specific Memory B and T-CD4+ Cells

    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

    SciScore is an automated tool that is designed to assist expert reviewers by finding and presenting formulaic information scattered throughout a paper in a standard, easy to digest format. SciScore checks for the presence and correctness of RRIDs (research resource identifiers), and for rigor criteria such as sex and investigator blinding. For details on the theoretical underpinning of rigor criteria and the tools shown here, including references cited, please follow this link.

  2. Version published to 10.1101/2021.12.21.473528v1 on bioRxiv