Naive human B cells engage the receptor binding domain of SARS-CoV-2, variants of concern, and related sarbecoviruses

  1. Jared Feldman
  2. Julia Bals
  3. Clara G. Altomare
  4. Kerri St. Denis
  5. Evan C. Lam
  6. Blake M. Hauser
  7. Larance Ronsard
  8. Maya Sangesland
  9. Thalia Bracamonte Moreno
  10. Vintus Okonkwo
  11. Nathania Hartojo
  12. Alejandro B. Balazs
  13. Goran Bajic
  14. Daniel Lingwood
  15. Aaron G. Schmidt

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Abstract

Exposure to a pathogen elicits an adaptive immune response aimed to control and eradicate. Interrogating the abundance and specificity of the naive B cell repertoire contributes to understanding how to potentially elicit protective responses. Here, we isolated naive B cells from 8 seronegative human donors targeting the SARS-CoV-2 receptor-binding domain (RBD). Single B cell analysis showed diverse gene usage with no restricted complementarity determining region lengths. We show that recombinant antibodies engage SARS-CoV-2 RBD, circulating variants, and pre-emergent coronaviruses. Representative antibodies signal in a B cell activation assay and can be affinity matured through directed evolution. Structural analysis of a naive antibody in complex with spike shows a conserved mode of recognition shared with infection-induced antibodies. Lastly, both naive and affinity-matured antibodies can neutralize SARS-CoV-2. Understanding the naive repertoire may inform potential responses recognizing variants or emerging coronaviruses enabling the development of pan-coronavirus vaccines aimed at engaging germline responses.

One Sentence Summary

Isolation of antibody germline precursors targeting the receptor binding domain of coronaviruses.

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  1. ScreenIT

    SciScore for 10.1101/2021.02.02.429458: (What is this?)

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

    Table 1: Rigor

    Institutional Review Board StatementIACUC: All experiments were conducted with MGH Institutional Biosafety Committee approval (MGH protocol
    IRB: Additionally, the control convalescent sera used for ELISA was obtained under the approved Partners Institutional Review Board (protocol 2020P000895) for use of patient samples for the development and validation of SARS-CoV-2 diagnostic tests (9).
    Randomizationnot detected.
    Blindingnot detected.
    Power Analysisnot detected.
    Sex as a biological variablenot detected.
    Cell Line Authenticationnot detected.

    Table 2: Resources

    Experimental Models: Cell Lines
    SentencesResources
    ACE-2 cell binding assay: ACE-2 expressing 293T cells were incubated with 200 nM of RBD antigen in PBS for 1hr on ice.
    ACE-2
    suggested: None
    293T
    suggested: None
    The titers of viral supernatants were determined via flow cytometry on 293T-ACE2 cells (72) and via the HIV-1 p24CA antigen capture assay (Leidos Biomedical Research, Inc.).
    293T-ACE2
    suggested: RRID:CVCL_YZ65)
    Software and Algorithms
    SentencesResources
    (GraphPad Software).
    GraphPad
    suggested: (GraphPad Prism, RRID:SCR_002798)
    Flow cytometry data was analyzed using FlowJo software version 10.7.1.
    FlowJo
    suggested: (FlowJo, RRID:SCR_008520)
    Data were analyzed using Graphpad Prism.
    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: 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 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 10.1101/2021.02.02.429458 on bioRxiv