MHC-II constrains the natural neutralizing antibody response to the SARS-CoV-2 spike RBM in humans

  1. Andrea Castro
  2. Kivilcim Ozturk
  3. Maurizio Zanetti
  4. Hannah Carter

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Abstract

SARS-CoV-2 antibodies develop within two weeks of infection, but wane relatively rapidly post-infection, raising concerns about whether antibody responses will provide protection upon re-exposure. Here we revisit T-B cooperation as a prerequisite for effective and durable neutralizing antibody responses centered on a mutationally constrained RBM B cell epitope. T-B cooperation requires co-processing of B and T cell epitopes by the same B cell and is subject to MHC-II restriction. We evaluated MHC-II constraints relevant to the neutralizing antibody response to a mutationally-constrained B cell epitope in the receptor binding motif (RBM) of the spike protein. Examining common MHC-II alleles, we found that peptides surrounding this key B cell epitope are predicted to bind poorly, suggesting a lack MHC-II support in T-B cooperation, impacting generation of high-potency neutralizing antibodies in the general population. Additionally, we found that multiple microbial peptides had potential for RBM cross-reactivity, supporting previous exposures as a possible source of T cell memory.

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  1. ScreenIT

    SciScore for 10.1101/2020.12.26.424449: (What is this?)

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

    Table 1: Rigor

    Institutional Review Board Statementnot detected.
    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
    The SARS1, MERS1, HCoV-229E, HCoV-NL63, HCoV-OC43, and HCoV-HKU1 spike protein sequences were also downloaded from UniProt (P59594, K9N5Q8, P15423, Q6Q1S2, P36334, Q0ZME7, respectively).
    HCoV-NL63
    suggested: RRID:CVCL_RW88)
    Software and Algorithms
    SentencesResources
    Multiple sequence alignment was performed on the EMBL-EBI Clustal Omega web server using default parameters (70).
    Clustal Omega
    suggested: (Clustal Omega, RRID:SCR_001591)
    BLAST analysis: 15mers were generated along a sliding window +/− 30 amino acids from the FNCY patch start and end (455-518, 0-index) and input into NCBI BLAST (74) using the ‘refseq_protein’ database and excluding SARS-CoV-2 (taxid:2697049).
    BLAST
    suggested: (BLASTX, RRID:SCR_001653)

    Results from OddPub: Thank you for sharing your code and 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: 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.

    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 10.1101/2020.12.26.424449 on bioRxiv