Dynamic Change and Clinical Relevance of Postinfectious SARS-CoV-2 Antibody Responses

  1. Patrick W G Mallon
  2. Willard Tinago
  3. Alejandro Garcia Leon
  4. Kathleen McCann
  5. Grace Kenny
  6. Padraig McGettrick
  7. Sandra Green
  8. Rosanna Inzitari
  9. Aoife G Cottere
  10. Eoin R Feeney
  11. Stefano Savinelli
  12. Peter Doran
  13. All Ireland Infectious Diseases Cohort Study Group
  14. P Gavin
  15. J Eustace
  16. M Horgan
  17. C Sadlier
  18. J Lambert
  19. T McGinty
  20. J Low
  21. B Whelan
  22. B McNicholas
  23. O Yousif
  24. G Courtney
  25. E DeBarra
  26. C Kelly
  27. T Bracken

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Abstract

Background

Although reports suggest that most individuals with coronavirus disease 2019 (COVID-19) develop detectable antibodies postinfection, the kinetics, durability, and relative differences between immunoglobulin M (IgM) and immunoglobulin G (IgG) responses beyond the first few weeks after symptom onset remain poorly understood.

Methods

Within a large, well-phenotyped, diverse, prospective cohort of subjects with and without severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) polymerase chain reaction (PCR)–confirmed infection and historical controls derived from cohorts with high prevalence of viral coinfections and samples taken during prior flu seasons, we measured SARS-CoV-2 serological responses (both IgG and IgM) using commercially available assays. We calculated sensitivity, specificity, and relationship with disease severity and mapped the kinetics of antibody responses over time using generalized additive models.

Results

We analyzed 1001 samples from 752 subjects, 327 with confirmed SARS-CoV-2 (29.7% with severe disease) spanning a period of 90 days from symptom onset. Sensitivity was lower (44.1%–47.1%) early (<10 days) after symptom onset but increased to >80% after 10 days. IgM positivity increased earlier than IgG-targeted assays, but positivity peaked between days 32 and 38 post–onset of symptoms and declined thereafter, a dynamic that was confirmed when antibody levels were analyzed, with a more rapid decline observed with IgM. Early (<10 days) IgM but not IgG levels were significantly higher in those who subsequently developed severe disease (signal/cutoff 4.20 [0.75–17.93] vs 1.07 [0.21–5.46]; P = .048).

Conclusions

This study suggests that postinfectious antibody responses in those with confirmed COVID-19 begin to decline relatively early postinfection and suggests a potential role for higher IgM levels early in infection in the prediction of subsequent disease severity.

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  1. Version published to 10.1093/ofid/ofab122
  2. ScreenIT

    SciScore for 10.1101/2021.01.24.20248381: (What is this?)

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

    Table 1: Rigor

    Institutional Review Board StatementConsent: All subjects provide written, informed consent and the study is approved by local and national research ethics committees.
    IRB: All subjects provide written, informed consent and the study is approved by local and national research ethics committees.
    Randomizationnot detected.
    Blinding18, 19] Laboratory analysis: Plasma, stored at −80°C and thawed in batches, underwent same-day serological testing in the Core Laboratory in the Clinical Research Centre, University College Dublin, Ireland by blinded technicians using four assays according to manufacturers’ instructions: the Elecsys® anti-SARS-CoV-2 electrochemiluminescence immunoassay (Roche Diagnostics, Penzberg, Germany) run on the Cobas® e411 automated platform (Roche Diagnostics), the SARS-CoV-2 IgG chemiluminescent microparticle immunoassay (CMIA) (Abbott Laboratories, IL, USA) run on both the Architect i2000SR platform (Abbott Diagnostics), the Abbott Alinity ci platform (Abbott Diagnostics) and the Abbott SARS-CoV-2 IgM assay run on the Abbott Architect i2000SR platform.
    Power Analysisnot detected.
    Sex as a biological variablenot detected.

    Table 2: Resources

    Antibodies
    SentencesResources
    The Elecsys assay is a sandwich immunoassay that detects IgA, IgM and IgG antibodies to SARS-CoV-2, so a positive result may reflect reactive, non-IgG antibody responses.
    IgG
    suggested: None
    SARS-CoV-2
    suggested: None
    Software and Algorithms
    SentencesResources
    18, 19] Laboratory analysis: Plasma, stored at −80°C and thawed in batches, underwent same-day serological testing in the Core Laboratory in the Clinical Research Centre, University College Dublin, Ireland by blinded technicians using four assays according to manufacturers’ instructions: the Elecsys® anti-SARS-CoV-2 electrochemiluminescence immunoassay (Roche Diagnostics, Penzberg, Germany) run on the Cobas® e411 automated platform (Roche Diagnostics), the SARS-CoV-2 IgG chemiluminescent microparticle immunoassay (CMIA) (Abbott Laboratories, IL, USA) run on both the Architect i2000SR platform (Abbott Diagnostics), the Abbott Alinity ci platform (Abbott Diagnostics) and the Abbott SARS-CoV-2 IgM assay run on the Abbott Architect i2000SR platform.
    Abbott Laboratories
    suggested: None
    Abbott
    suggested: (Abbott, RRID:SCR_010477)
    Abbott Architect
    suggested: (Abbott ARCHITECT i1000sr System, RRID:SCR_019328)

    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: We detected the following sentences addressing limitations in the study:
    Our study has limitations. Although we measured serological responses, we do not have data on corresponding functional immunity, important when interpreting the clinical relevance of the observed decline in antibody levels. Although we analysed historical samples, we did not have data on confirmed influenza in these subjects nor did we routinely test the SARS-CoV2 Pos and Neg groups for other co-infections. Despite these limitations, this study, one of the largest and most detailed analyses of the performance and kinetics of anti-SARS-CoV-2 antibody responses, suggests higher, early IgM responses in those who develop more severe COVID-19. The early decline in antibody levels, as early as five weeks post symptom onset, contribute to an increasing concern that post-infectious immunity to SARS-CoV-2 infection may be time limited.

    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.

  3. Version published to 10.1101/2021.01.24.20248381 on medRxiv