Dynamics and significance of the antibody response to SARS-CoV-2 infection

  1. Anita S. Iyer
  2. Forrest K. Jones
  3. Ariana Nodoushani
  4. Meagan Kelly
  5. Margaret Becker
  6. Damien Slater
  7. Rachel Mills
  8. Erica Teng
  9. Mohammad Kamruzzaman
  10. Wilfredo F. Garcia-Beltran
  11. Michael Astudillo
  12. Diane Yang
  13. Tyler E. Miller
  14. Elizabeth Oliver
  15. Stephanie Fischinger
  16. Caroline Atyeo
  17. A. John Iafrate
  18. Stephen B. Calderwood
  19. Stephen A. Lauer
  20. Jingyou Yu
  21. Zhenfeng Li
  22. Jared Feldman
  23. Blake M. Hauser
  24. Timothy M. Caradonna
  25. John A. Branda
  26. Sarah E. Turbett
  27. Regina C. LaRocque
  28. Guillaume Mellon
  29. Dan H. Barouch
  30. Aaron G. Schmidt
  31. Andrew S. Azman
  32. Galit Alter
  33. Edward T Ryan
  34. Jason B. Harris
  35. Richelle C. Charles

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Abstract

BACKGROUND

Characterizing the humoral immune response to SARS-CoV-2 and developing accurate serologic assays are needed for diagnostic purposes and estimating population-level seroprevalence.

METHODS

We measured the kinetics of early antibody responses to the receptor-binding domain (RBD) of the spike (S) protein of SARS-CoV-2 in a cohort of 259 symptomatic North American patients infected with SARS-CoV-2 (up to 75 days after symptom onset) compared to antibody levels in 1548 individuals whose blood samples were obtained prior to the pandemic.

RESULTS

Between 14-28 days from onset of symptoms, IgG, IgA, or IgM antibody responses to RBD were all accurate in identifying recently infected individuals, with 100% specificity and a sensitivity of 97%, 91%, and 81% respectively. Although the estimated median time to becoming seropositive was similar across isotypes, IgA and IgM antibodies against RBD were short-lived with most individuals estimated to become seronegative again by 51 and 47 days after symptom onset, respectively. IgG antibodies against RBD lasted longer and persisted through 75 days post-symptoms. IgG antibodies to SARS-CoV-2 RBD were highly correlated with neutralizing antibodies targeting the S protein. No cross-reactivity of the SARS-CoV-2 RBD-targeted antibodies was observed with several known circulating coronaviruses, HKU1, OC 229 E, OC43, and NL63.

CONCLUSIONS

Among symptomatic SARS-CoV-2 cases, RBD-targeted antibodies can be indicative of previous and recent infection. IgG antibodies are correlated with neutralizing antibodies and are possibly a correlate of protective immunity.

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  1. ScreenIT

    SciScore for 10.1101/2020.07.18.20155374: (What is this?)

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

    Table 1: Rigor

    Institutional Review Board StatementIRB: All research was approved by the Institutional Review Board for Human Subjects Research at MGH
    Randomizationnot detected.
    Blindingnot detected.
    Power Analysisnot detected.
    Sex as a biological variablenot detected.

    Table 2: Resources

    Antibodies
    SentencesResources
    Anti- RBD-specific antibody concentrations (ug/mL) were quantified using isotype-specific anti-RBD monoclonal antibodies5.
    Anti- RBD-specific
    suggested: None
    anti-RBD
    suggested: None
    antibodies5
    suggested: None

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

    Results from LimitationRecognizer: We detected the following sentences addressing limitations in the study:
    One notable limitation of our study was that our cohort of individuals with SARS-CoV-2 infection was skewed toward adults with clinically significant disease or with risk factors for disease progression. Individuals with mild or asymptomatic infection have been shown to develop less robust antibody responses13, which may lead to false negatives if our proposed assay thresholds are used. Individuals with mild or asymptomatic infection may also serorevert quicker than symptomatic individuals13. The gradation of responses by disease severity has been found in other infections, including SARS-CoV-213 and MERS-CoV infection16. An association between disease severity and the kinetics of the antibody response is also suggested by our finding that individuals with more severe disease, who required ICU-level care, seroconverted earlier than individuals who did not require ICU-level support. It is important to note that our assay identifies individuals with recent SARS-CoV-2 infection but does not provide information about whether individuals are protected from subsequent infection. Optimal immunologic correlates of protection for SARS-CoV-2 remain unknown in humans. In many human challenge studies of common cold coronavirus infection, the presence of pre-existing neutralizing antibodies has been associated with protection against the development of symptomatic infection and with decreased viral shedding17. In addition, in vaccinated rhesus macaques challenged with SARS-CoV-2 infection...

    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. ScreenIT

    SciScore for 10.1101/2020.07.18.20155374: (What is this?)

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

    Table 1: Rigor

    Institutional Review Board StatementAll research was approved by the Institutional Review Board for Human Subjects Research at MGHRandomizationnot detected.Blindingnot detected.Power Analysisnot detected.Sex as a biological variableThe majority of SARS-CoV-2 positive cases were severe (95% hospitalized, 31% requiring ICU level care, 16% died), male (62%), and older (median age: 58) (Table 1, Figure S1).

    Table 2: Resources

    Antibodies
    SentencesResources
    RESULTS Between 14-28 days from onset of symptoms, IgG, IgA, or IgM antibody responses to RBD were all accurate in identifying recently infected individuals, with 100% specificity and a sensitivity of 97%, 91%, and 81% respectively.
    IgM
    suggested: None
    Anti- RBD-specific antibody concentrations (ug/mL) were quantified using isotype-specific anti-RBD monoclonal antibodies5.
    Anti- RBD-specific
    suggested: None
          <div style="margin-bottom:8px">
        <div><b>antibodies5</b></div>
        <div>suggested: None</div>
      </div>
    </td></tr><tr><td style="min-width:100px;vertical-align:top;border-bottom:1px solid lightgray">Kinetics of anti-SARS-CoV-2 RBD antibody responses.</td><td style="min-width:100px;border-bottom:1px solid lightgray">
      <div style="margin-bottom:8px">
        <div><b>anti-SARS-CoV-2 RBD</b></div>
        <div>suggested: None</div>
      </div>
    </td></tr><tr><td style="min-width:100px;vertical-align:top;border-bottom:1px solid lightgray">These models provide an estimate of the contribution of each antibody isotype, as well as the maximum predictive value of combined measures of anti-RBD IgG, IgA and IgM responses.</td><td style="min-width:100px;border-bottom:1px solid lightgray">
      <div style="margin-bottom:8px">
        <div><b>anti-RBD IgG</b></div>
        <div>suggested: None</div>
      </div>
    </td></tr><tr><td style="min-width:100px;vertical-align:top;border-bottom:1px solid lightgray">Using the pre-determined thresholds for seropositivity for each antibody isotype, out of the 223 patients with samples collected during early infection (< 14 days post symptom onset), we were able to identify an additional 14 cases by adding IgM, 15 by adding IgA, and 23 by adding both IgM and IgA.</td><td style="min-width:100px;border-bottom:1px solid lightgray">
      <div style="margin-bottom:8px">
        <div><b>IgA</b></div>
        <div>suggested: None</div>
      </div>
    </td></tr><tr><td style="min-width:100px;vertical-align:top;border-bottom:1px solid lightgray">We evaluated antibody responses to RBDs derived from spike proteins of endemic human coronaviruses (CoVs) (i.e. HKU1, CoV OC 229E, OC43, and NL63), severe acute respiratory syndrome coronavirus (SARS-CoV-1) and Middle East Respiratory Syndrome coronavirus (MERS-CoV) (Figure S6).</td><td style="min-width:100px;border-bottom:1px solid lightgray">
      <div style="margin-bottom:8px">
        <div><b>NL63</b></div>
        <div>suggested: None</div>
      </div>
    
      <div style="margin-bottom:8px">
        <div><b>SARS-CoV-1</b></div>
        <div>suggested: None</div>
      </div>
    </td></tr><tr><td style="min-width:100px;vertical-align:top;border-bottom:1px solid lightgray">We did not observe a cross-reactive response to the endemic human coronaviruses in individuals infected with SARSCoV-2, and antibody responses to these CoVs were comparable between pre-pandemic controls and individuals with COVID-19 at all phases of infection.</td><td style="min-width:100px;border-bottom:1px solid lightgray">
      <div style="margin-bottom:8px">
        <div><b>SARSCoV-2</b></div>
        <div>suggested: None</div>
      </div>
    </td></tr><tr><td style="min-width:100px;vertical-align:top;border-bottom:1px solid lightgray">Nonetheless, it is notable that antiRBD IgG antibodies were strongly correlated with the neutralizing antibodies associated with protection in vaccinated macaques6.</td><td style="min-width:100px;border-bottom:1px solid lightgray">
      <div style="margin-bottom:8px">
        <div><b>antiRBD IgG</b></div>
        <div>suggested: None</div>
      </div>
    </td></tr><tr><td style="min-width:100px;vertical-align:top;border-bottom:1px solid lightgray">Our results, therefore, provide strong support for the application of anti-RBD antibodies as a marker of recent SARS-CoV-2 infection.</td><td style="min-width:100px;border-bottom:1px solid lightgray">
      <div style="margin-bottom:8px">
        <div><b>anti-RBD</b></div>
        <div>suggested: None</div>
      </div>
    </td></tr></table>

    Data from additional tools added to each annotation on a weekly basis.

    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 is not a substitute for expert review. SciScore checks for the presence and correctness of RRIDs (research resource identifiers) in the manuscript, and detects sentences that appear to be missing RRIDs. SciScore also checks to make sure that rigor criteria are addressed by authors. It does this by detecting sentences that discuss criteria such as blinding or power analysis. SciScore does not guarantee that the rigor criteria that it detects are appropriate for the particular study. Instead it assists authors, editors, and reviewers by drawing attention to sections of the manuscript that contain or should contain various rigor criteria and key resources. For details on the results shown here, including references cited, please follow this link.

  3. Version published to 10.1101/2020.07.18.20155374v1 on medRxiv