Immune recall improves antibody durability and breadth to SARS-CoV-2 variants

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Abstract

Key features of immune memory are greater and faster antigen-specific antibody responses to repeat infection. In the setting of immune-evading viral evolution, it is important to understand how far antibody memory recognition stretches across viral variants when memory cells are recalled to action by repeat invasions. It is also important to understand how immune recall influences longevity of secreted antibody responses. We analyzed SARS-CoV-2 variant recognition; dynamics of memory B cells; and secreted antibody over time after infection, vaccination, and boosting. We find that a two-dose SARS-CoV-2 vaccination regimen given after natural infection generated greater longitudinal antibody stability and induced maximal antibody magnitudes with enhanced breadth across Beta, Gamma, Delta and Omicron variants. A homologous third messenger RNA vaccine dose in COVID-naïve individuals conferred greater cross-variant evenness of neutralization potency with stability that was equal to the hybrid immunity conferred by infection plus vaccination. Within unvaccinated individuals who recovered from COVID, enhanced antibody stability over time was observed within a subgroup of individuals who recovered more quickly from COVID and harbored significantly more memory B cells cross-reactive to endemic coronaviruses early after infection. These cross-reactive clones map to the conserved S2 region of SARS-CoV-2 spike with higher somatic hypermutation levels and greater target affinity. We conclude that SARS-CoV-2 antigen challenge histories in humans influence not only the speed and magnitude of antibody responses but also functional cross-variant antibody repertoire composition and longevity.

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  1. SciScore for 10.1101/2021.09.09.459504: (What is this?)

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

    Table 1: Rigor

    EthicsIRB: Human subjects: Mass General Brigham Institutional Review Board approved this study and protocol.
    Sex as a biological variablenot detected.
    Randomizationnot detected.
    Blindingnot detected.
    Power Analysisnot detected.
    Cell Line Authenticationnot detected.

    Table 2: Resources

    Antibodies
    SentencesResources
    For the anti-S and anti-RBD antibody standard, the monoclonal antibody CR3022 was serially diluted 2 times from 0.5 μg/mL.
    anti-S
    suggested: None
    anti-RBD
    suggested: None
    Cells were stained with Biolegend antibodies FITC anti-CD27 (356404), PE anti-CCR7 (353204), Percp
    anti-CD27
    suggested: (BioLegend Cat# 356404, RRID:AB_2561788)
    anti-CCR7
    suggested: None
    Experimental Models: Cell Lines
    SentencesResources
    Cell lines: HEK293T cell line (ATCC) was maintained in DMEM containing 10% FBS, 100 U/mL penicillin and 100 U/mL streptomycin (Gibco).
    HEK293T
    suggested: None
    SARS-CoV-2 pseudovirus neutralization assay: 293T cells were co-transfected with pHDM vector expressing SARS-CoV-2 variants, pLenti CMV Puro LUC (w168-1), and psPAX2 (Addgene) with lipofetamine 3000.
    293T
    suggested: None
    Recombinant DNA
    SentencesResources
    To be consistent with the pHDM-Wuhan-Hu-1-delta21 and pHDM-D614G-delta21 plasmids obtained from Addgene, the c-terminal 21 amino acid on all the variants were deleted (Crawford et al., 2020).
    pHDM-Wuhan-Hu-1-delta21
    suggested: None
    pHDM-D614G-delta21
    suggested: None
    Binding signals were scored positive if OD405 values were above 5x PBS control on the same plate. mAb spike binding EC50 measurement: 293T cells were co-transfected with pHDM-Wuhan-Hu-1 and pMAX-GFP plasmids at a 4:1 ratio by lipofectamine 3000 (Thermo fisher).
    pHDM-Wuhan-Hu-1
    suggested: None
    pMAX-GFP
    suggested: RRID:Addgene_16007)
    293T cell pool cotransfected with pHEF-VsVg and pMAX-GFP plasmids at a 4:1 ratio was used as a negative control.
    pHEF-VsVg
    suggested: RRID:Addgene_22501)
    SARS-CoV-2 pseudovirus neutralization assay: 293T cells were co-transfected with pHDM vector expressing SARS-CoV-2 variants, pLenti CMV Puro LUC (w168-1), and psPAX2 (Addgene) with lipofetamine 3000.
    pHDM
    suggested: None
    psPAX2
    suggested: RRID:Addgene_12260)
    Software and Algorithms
    SentencesResources
    After enrollment, clinical team identified one subject was not diagnosed by nasopharyngeal swab RT-PCR test, but by Quest Diagnostics antibody test and symptoms consistent with COVID-19 (Chen et al., 2020).
    Quest
    suggested: (QUEST, RRID:SCR_005210)
    Graphpad software generated standard curves for each plate by non-linear regression.
    Graphpad
    suggested: (GraphPad, RRID:SCR_000306)
    The EC50 for each S-binding mAb was reported as the concentration with 50% of maximal binding determined by non-linear regression 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 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.