Evolution of immune responses to SARS-CoV-2 in mild-moderate COVID-19

  1. Adam K. Wheatley
  2. Jennifer A. Juno
  3. Jing J. Wang
  4. Kevin J. Selva
  5. Arnold Reynaldi
  6. Hyon-Xhi Tan
  7. Wen Shi Lee
  8. Kathleen M. Wragg
  9. Hannah G. Kelly
  10. Robyn Esterbauer
  11. Samantha K. Davis
  12. Helen E. Kent
  13. Francesca L. Mordant
  14. Timothy E. Schlub
  15. David L. Gordon
  16. David S. Khoury
  17. Kanta Subbarao
  18. Deborah Cromer
  19. Tom P. Gordon
  20. Amy W. Chung
  21. Miles P. Davenport
  22. Stephen J. Kent

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Abstract

The durability of infection-induced SARS-CoV-2 immunity has major implications for reinfection and vaccine development. Here, we show a comprehensive profile of antibody, B cell and T cell dynamics over time in a cohort of patients who have recovered from mild-moderate COVID-19. Binding and neutralising antibody responses, together with individual serum clonotypes, decay over the first 4 months post-infection. A similar decline in Spike-specific CD4 + and circulating T follicular helper frequencies occurs. By contrast, S-specific IgG + memory B cells consistently accumulate over time, eventually comprising a substantial fraction of circulating the memory B cell pool. Modelling of the concomitant immune kinetics predicts maintenance of serological neutralising activity above a titre of 1:40 in 50% of convalescent participants to 74 days, although there is probably additive protection from B cell and T cell immunity. This study indicates that SARS-CoV-2 immunity after infection might be transiently protective at a population level. Therefore, SARS-CoV-2 vaccines might require greater immunogenicity and durability than natural infection to drive long-term protection.

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  1. ScreenIT

    SciScore for 10.1101/2020.09.09.20191205: (What is this?)

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

    Table 1: Rigor

    NIH rigor criteria are not applicable to paper type.

    Table 2: Resources

    Antibodies
    SentencesResources
    SARS-CoV-2- specific antibodies were detected using phycoerythrin (PE)-conjugated mouse anti-human pan-IgG, IgG1, IgG2, IgG3, IgA1 or IgA2 (Southern Biotech) at 1.3μg/ml, 25μl per well.
    anti-human pan-IgG, IgG1
    suggested: None
    IgG2, IgG3
    suggested: None
    IgA1
    suggested: None
    IgA2
    suggested: None
    RBD neutralising human IgG1 antibody (ACROBiosystems, USA) was included as a positive control, in addition to COVID-19 negative plasma and buffer only negative controls.
    human IgG1
    suggested: None
    Monoclonal antibodies for surface staining included: CD19-ECD (J3-119) (Beckman Coulter), CD20 Alexa700 (2H7), IgM-BUV395 (G20-127), CD21-BUV737 (B-ly4), IgDCy7PE (IA6-2), IgG-BV786 (G18-145) (BD), CD14-BV510 (M5E2), CD3-BV510 (OKT3), CD8a-BV510 (RPA-T8), CD16-BV510 (3G8), CD10-BV510 (HI10a), CD27-BV605 (O323) (Biolegend), IgA-Vio450 (clone) (Miltenyi).
    CD20
    suggested: (BD Biosciences Cat# 740204, RRID:AB_2739954)
    CD21-BUV737
    suggested: None
    CD14-BV510
    suggested: None
    CD3-BV510
    suggested: None
    OKT3
    suggested: (BD Biosciences Cat# 566779, RRID:AB_2869862)
    CD8a-BV510
    suggested: None
    CD16-BV510
    suggested: None
    CD10-BV510
    suggested: None
    CD27-BV605
    suggested: None
    IgA-Vio450
    suggested: None
    Following stimulation, cells were washed, stained with Live/dead Blue viability dye (ThermoFisher), and a cocktail of monoclonal antibodies: CD27 BUV737 (L128), CD45RA PeCy7 (HI100), CD20 BUV805 (2H7), (BD Biosciences), CD3 BV510 (SK7), CD4 BV605 (RPA-T4), CD8 BV650 (RPA-T8)
    CD27
    suggested: (BD Biosciences Cat# 751682, RRID:AB_2875668)
    CD45RA
    suggested: (BD Biosciences Cat# 742052, RRID:AB_2871341)
    CD3
    suggested: None
    CD4
    suggested: None
    CD8
    suggested: None
    Experimental Models: Cell Lines
    SentencesResources
    Microneutralisation Assay: SARS-CoV-2 isolate CoV/Australia/VIC01/202042 was passaged in Vero cells and stored at −80C.
    Vero
    suggested: None
    The ectodomain of SARS-CoV-2 (isolate WHU1;residues 1 – 1208) was synthesised with furin cleavage site removed and P986/987 stabilisation mutations45, a C-terminal T4 trimerisation domain, Avitag and His-tag, expressed in Expi293 cells and purified by Ni-NTA affinity and size-exclusion chromatography using a Superose 6 16/70 column (GE Healthcare).
    Expi293
    suggested: RRID:CVCL_D615)
    Software and Algorithms
    SentencesResources
    Comparison of B and T cell frequencies at first and final sampling was performed using Wilcoxon Rank Sum test in GraphPad Prism 8.
    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 found bar graphs of continuous data. We recommend replacing bar graphs with more informative graphics, as many different datasets can lead to the same bar graph. The actual data may suggest different conclusions from the summary statistics. For more information, please see Weissgerber et al (2015).

    Results from JetFighter: Please consider improving the rainbow (“jet”) colormap(s) used on pages 52 and 31. At least one figure is not accessible to readers with colorblindness and/or is not true to the data, i.e. not perceptually uniform.

    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 10.1038/s41467-021-21444-5
  3. Version published to 10.1101/2020.09.09.20191205v2 on medRxiv
  4. Version published to 10.1101/2020.09.09.20191205v1 on medRxiv