Immunological memory to SARS-CoV-2 assessed for up to eight months after infection

  1. Jennifer M. Dan
  2. Jose Mateus
  3. Yu Kato
  4. Kathryn M. Hastie
  5. Esther Dawen Yu
  6. Caterina E. Faliti
  7. Alba Grifoni
  8. Sydney I. Ramirez
  9. Sonya Haupt
  10. April Frazier
  11. Catherine Nakao
  12. Vamseedhar Rayaprolu
  13. Stephen A. Rawlings
  14. Bjoern Peters
  15. Florian Krammer
  16. Viviana Simon
  17. Erica Ollmann Saphire
  18. Davey M. Smith
  19. Daniela Weiskopf
  20. Alessandro Sette
  21. Shane Crotty

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Abstract

Understanding immune memory to SARS-CoV-2 is critical for improving diagnostics and vaccines, and for assessing the likely future course of the COVID-19 pandemic. We analyzed multiple compartments of circulating immune memory to SARS-CoV-2 in 254 samples from 188 COVID-19 cases, including 43 samples at ≥ 6 months post-infection. IgG to the Spike protein was relatively stable over 6+ months. Spike-specific memory B cells were more abundant at 6 months than at 1 month post symptom onset. SARS-CoV-2-specific CD4 + T cells and CD8 + T cells declined with a half-life of 3-5 months. By studying antibody, memory B cell, CD4 + T cell, and CD8 + T cell memory to SARS-CoV-2 in an integrated manner, we observed that each component of SARS-CoV-2 immune memory exhibited distinct kinetics.

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  3. ScreenIT

    SciScore for 10.1101/2020.11.15.383323: (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.

    Table 2: Resources

    Software and Algorithms
    SentencesResources
    Materials and Methods Figures S1-S10 Tables S1-S2 Data File Materials and Methods:
    Methods
    suggested: None

    Results from OddPub: Thank you for sharing your 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.

  4. Version published to 10.1101/2020.11.15.383323v2 on bioRxiv
  5. ScreenIT

    SciScore for 10.1101/2020.11.15.383323: (What is this?)

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

    Table 1: Rigor

    Institutional Review Board StatementMETHODS Human Subjects The Institutional Review Boards of the University of California, San Diego (UCSD; 200236X) and the La Jolla Institute for Immunology (LJI; VD-214) approved the protocols used for blood collection for subjects with COVID-19 who donated at all sites other than Mt. Sinai. The Icahn School of Medicine at Mt. Sinai IRB approved the samples collected at this institution in New York City (Randomizationnot detected.Blindingnot detected.Power Analysisnot detected.Sex as a biological variableSubjects (43% male, 57% female) represented a range of asymptomatic, mild, moderate, and severe COVID-19 cases (Table S1), and were recruited from multiple sites throughout the United States.Cell Line Authenticationnot detected.

    Table 2: Resources

    Antibodies
    SentencesResources
    The percentage of subjects seropositive for SARS-CoV-2 neutralizing antibodies (titer > 20) at 6 to 8 months PSO was 90% (36/40).
    SARS-CoV-2 neutralizing antibodies (titer > 20
    suggested: None
    For IgG, anti-human IgG peroxidase antibody produced in goat (Sigma A6029) was used at a 1:5,000 dilution.
    anti-human IgG peroxidase antibody
    suggested: (Sigma-Aldrich Cat# A6029, RRID:AB_258272)
    anti-human IgG
    suggested: (Sigma-Aldrich Cat# A6029, RRID:AB_258272)
    For IgA, anti-human IgA horseradish peroxidase antibody (Hybridoma Reagent Laboratory HP6123-HRP) was used at a 1:1,000 dilution.
    anti-human IgA
    suggested: None
    Biotinylated spike was mixed with streptavidin BV421 (BioLegend, Cat# 405225) and streptavidin Alexa Fluor 647 (Thermo Fisher Scientific, Cat# S21374) at 20:1 ratio (~6:1 molar ratio). ~107 previously frozen PBMC samples were prepared in U-bottom 96-well plates and stained with 50µL antigen probe cocktail containing 100ng spike per probe (total 200ng), 27.5ng RBD, 40ng nucleocapsid per probe (total 80ng) and 20ng streptavidin PECy5.5 at 4°C for one hour to ensure maximal staining quality before surface staining with antibodies as listed in Table S2 was performed in Brilliant Buffer at 4°C for 30min.
    30min
    suggested: None
    Antibodies utilized in the CD8+ and CD4+ T cell activation induced markers (AIM) assays Membrane Antibody Fluorochrome Clone/vendor/catalog Dilution CD45RA BV421 HI100/BioLegend/304130 1:50 CD14 BUV563 M5E2/BD/741360 1:100 CD19 BUV805 HIB19/BD/742007 1:100 Live/Dead ef506/Aqua Thermo Fisher/65-0866-18 1:200 CD8 BV650 RPA-T8/BioLegend/301042 1:50 CD4 BV605 RPA-T4/BD/562658 1:25 CCR7 FITC G043H7/BioLegend/353216 1:50 CD69 PE FN50/BD/555531 1:10 OX40 PE-Cy7 Ber-ACT35/BioLegend/350012 1:50 CD137 APC 4B4-1/BioLegend/309810 1:25 CD3 AF700 UCHT1/Thermo Fisher/56-0038-42 1:25 SUPPLEMENTARY FIGURE LEGENDS Figure S1.
    CD14
    suggested: (BD Biosciences Cat# 741360, RRID:AB_2870860)
    Ber-ACT35/BioLegend/350012
    suggested: None
    CD3
    suggested: (Thermo Fisher Scientific Cat# 56-0038-42, RRID:AB_10597906)
    Three data points are outside the axis limits (C) The ratio of RBD-specific memory B cell frequency (percentage) relative to RBD IgA antibodies (pseudo-first order kinetic model, R2 = 0.3804).
    RBD IgA
    suggested: None
    R2
    suggested: None
    ( D) The ratio of SARS-CoV-2 specific CD4+ T cell frequency relative to RBD IgG antibodies (best-fit simple linear regression line, R2 = 0.0003891).
    RBD IgG
    suggested: (Thermo Fisher Scientific Cat# 703971, RRID:AB_2866480)
    Experimental Models: Cell Lines
    SentencesResources
    Briefly, Vero cells were seeded in 96 well plates to produce a monolayer at the time of infection.
    Vero
    suggested: None
    Pre-titrated amounts of rVSV-SARS-Cov-2 (phCMV3-SARS-CoV-2 spike SARS-CoV-2-pseduotyped VSV-ΔG-GFP were generated by transfecting 293T cells) were incubated with serially diluted human plasma at 37°C for hour before addition to confluent Vero monolayers in 96-well plates.
    293T
    suggested: None
    Software and Algorithms
    SentencesResources
    For gender analyses, modeling and t1/2 was performed similar to cross-sectional analyses; ANCOVA (VassarStats or GraphPad Prism 8.4) was then performed between male and female data sets.
    VassarStats
    suggested: (VassarStats, RRID:SCR_010263)
    GraphPad
    suggested: (GraphPad Prism, RRID:SCR_002798)
    Neutralization IC50 titers were calculated using One-Site Fit LogIC50 regression in GraphPad Prism 8.0.
    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.

    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.

  6. Version published to 10.1101/2020.11.15.383323v1 on bioRxiv