Effects of potent neutralizing antibodies from convalescent plasma in patients hospitalized for severe SARS-CoV-2 infection

  1. Arvind Gharbharan
  2. Carlijn C. E. Jordans
  3. Corine GeurtsvanKessel
  4. Jan G. den Hollander
  5. Faiz Karim
  6. Femke P. N. Mollema
  7. Janneke E. Stalenhoef – Schukken
  8. Anthonius Dofferhoff
  9. Inge Ludwig
  10. Adrianus Koster
  11. Robert-Jan Hassing
  12. Jeannet C. Bos
  13. Geert R. van Pottelberge
  14. Imro N. Vlasveld
  15. Heidi S. M. Ammerlaan
  16. Elena M. van Leeuwen – Segarceanu
  17. Jelle Miedema
  18. Menno van der Eerden
  19. Thijs J. Schrama
  20. Grigorios Papageorgiou
  21. Peter te Boekhorst
  22. Francis H. Swaneveld
  23. Yvonne M. Mueller
  24. Marco W. J. Schreurs
  25. Jeroen J. A. van Kampen
  26. Barry Rockx
  27. Nisreen M. A. Okba
  28. Peter D. Katsikis
  29. Marion P. G. Koopmans
  30. Bart L. Haagmans
  31. Casper Rokx
  32. Bart J. A. Rijnders

Reviewed by

Read the full article See related articles

Listed in

Log in to save this article

Abstract

In a randomized clinical trial of 86 hospitalized COVID-19 patients comparing standard care to treatment with 300mL convalescent plasma containing high titers of neutralizing SARS-CoV-2 antibodies, no overall clinical benefit was observed. Using a comprehensive translational approach, we unravel the virological and immunological responses following treatment to disentangle which COVID-19 patients may benefit and should be the focus of future studies. Convalescent plasma is safe, does not improve survival, has no effect on the disease course, nor does plasma enhance viral clearance in the respiratory tract, influence SARS-CoV-2 antibody development or serum proinflammatory cytokines levels. Here, we show that the vast majority of patients already had potent neutralizing SARS-CoV-2 antibodies at hospital admission and with comparable titers to carefully selected plasma donors. This resulted in the decision to terminate the trial prematurely. Treatment with convalescent plasma should be studied early in the disease course or at least preceding autologous humoral response development.

Article activity feed

  1. Version published to 10.1038/s41467-021-23469-2
  2. ScreenIT

    SciScore for 10.1101/2020.07.01.20139857: (What is this?)

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

    Table 1: Rigor

    Institutional Review Board StatementIRB: The study was reviewed and approved by the institutional review board of the Erasmus University Medical Center.
    Consent: Written informed consent was obtained from every patient or a legal patient representative.
    RandomizationStudy design: The ConCOVID study was designed as a nationwide multicenter open-label randomized clinical trial.
    Blindingnot detected.
    Power AnalysisWe previously showed that a positive total Ig or a IgM with an optical density (OD) ratio >10 (which equals an OD of 2.0), correlates closely with virus neutralizing antibody titers (PRNT50) of at least 1:80.17 Sample size and statistical analysis plan: With an anticipated 50% overall mortality reduction from 20% in the control arm, which was the reported mortality in hospitalized patients in the Netherlands when the protocol was designed and with a control to intervention ratio of 1:1, 426 patients were needed for the study to have 80% power with a global alpha level of 0.05 and adjusted alpha level for the primary endpoint of 0.0480, accounting for 1 interim analysis.
    Sex as a biological variablenot detected.

    Table 2: Resources

    Antibodies
    SentencesResources
    Of all donors tested, only plasma with anti-SARS-CoV-2 neutralizing antibodies confirmed by a SARS-COV-2 plaque reduction neutralization test (PRNT) and a PRNT50 titer of at least 1:80 was used.11 Furthermore, for each patient, we selected the plasma with the highest PRNT50 titer from the ABO compatible donor pool available at the time of inclusion.
    anti-SARS-CoV-2
    suggested: None

    Results from OddPub: Thank you for sharing your data.

    Results from LimitationRecognizer: We detected the following sentences addressing limitations in the study:
    This study has limitations. First, the premature ending of the study prevents definite conclusions regarding the clinical benefit of ConvP. Fortunately, a collaboration between several research groups evaluating ConvP is being formed and will allow for a pre-planned meta-analysis on pooled data from clinical trials. Our data do however show that ConvP should be studied earlier in the disease course. This could mean in the outpatient setting where ConvP could be evaluated in patients with a higher likelihood of disease progression based on clinical (e.g. age, comorbidities) or other (e.g. CRP, LDH) characteristics. Our data also show that in hospitalized patients testing for the presence of antibodies prior to ConvP should be part of the protocol, and stratifying or even excluding patients based on a positive antibody test will be needed. With the large variety of serological assays that have come available, it is important to carefully validate the assays prior to use and ideally correlate the assay to gold standard virus neutralization assays. Second, ConvP may have an effect that is unrelated to the neutralizing antibodies because therapy with intravenous immunoglobulines or plasma can have diverse anti-inflammatory and immunomodulatory effects as well. However, we considered any such effect unlikely because doses of Ig therapy when used as an immunomodulatory agent are typically at least 10-fold higher than the quantity of immunoglobulins in 300ml plasma. Finally, the rece...

    Results from TrialIdentifier: We found the following clinical trial numbers in your paper:

    IdentifierStatusTitle
    NCT04342182Active, not recruitingConvalescent Plasma as Therapy for Covid-19 Severe SARS-CoV-…

    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 10.21203/rs.3.rs-105265/v1 on Research Square
  4. ScreenIT

    SciScore for 10.1101/2020.07.01.20139857: (What is this?)

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

    Table 1: Rigor

    Institutional Review Board StatementThe institutional review board at Erasmus MC for their efficient review of the application and several amendments on short notice.RandomizationStructured abstract for full paper Methods The Convalescent-plasma-for-COVID ( ConCOVID ) study was a randomized trial comparing convalescent plasma with standard of care therapy in patients hospitalized for COVID-19 in the Netherlands .Blindingnot detected.Power AnalysisWe previously showed that a positive total Ig or a IgM with an optical density ( OD ) ratio >10 ( which equals an OD of 2.0) , correlates closely with virus neutralizing antibody titers ( PRNT50 ) of at least 1:80.17 Sample size and statistical analysis plan With an anticipated 50 % overall mortality reduction from 20 % in the control arm , which was the reported mortality in hospitalized patients in the Netherlands when the protocol was designed and with a control to intervention ratio of 1:1 , 426 patients were needed for the study to have 80 % power with a global alpha level of 0.05 and adjusted alpha level for the primary endpoint of 0.0480 , accounting for 1 interim analysis .Sex as a biological variableMost donor volunteers were males and part of the women were rejected as donor because of HLA/HNA antibodies.

    Table 2: Resources

    Antibodies
    SentencesResources
    Patients were randomized 1:1 and received 300ml of plasma with anti-SARSCoV-2 neutralizing antibody titers of at least 1:80 .
    anti-SARSCoV-2
    suggested: None
    Although symptomatic for only 10 days ( IQR 6-15 ) at the time of inclusion , 53 of 66 patients tested had anti-SARS-CoV-2 antibodies at baseline.
    anti-SARS-CoV-2
    suggested: None
    Of all donors tested , only plasma with antiSARS-CoV-2 neutralizing antibodies confirmed by a SARS-COV-2 plaque reduction neutralization test ( PRNT ) and a PRNT50 titer of at least 1:80 was used.11 Furthermore , for each patient , we selected the plasma with the highest PRNT50 titer from the ABO compatible donor pool available at the time of inclusion .
    antiSARS-CoV-2
    suggested: None
    Here as well we found that 26/37 (70%) of patients had anti-SARS-CoV-2 Ig antibodies and in 23/37 (62%) at a ratio >10, indicating high neutralization capacity.
    anti-SARS-CoV-2 Ig
    suggested: None
    However, many of the ongoing trials are not directly testing the neutralizing capacity of donor plasma (which is the gold standard in coronavirus serology), but rather rely on a positive anti-SARS-CoV-2 ELISA or do not test for antibodies at all.
    anti-SARS-CoV-2 ELISA
    suggested: None

    Results from LimitationRecognizer: We detected the following sentences addressing limitations in the study:

    • This study has limitations.
    • First, the premature ending of the study prevents definite conclusions regarding the clinical benefit of ConvP.
    • Fortunately, a collaboration between several research groups evaluating ConvP is being formed and will allow for a pre-planned meta-analysis on pooled data from clinical trials.
    • Our data do however show that ConvP should be studied earlier in the disease course.
    • This could mean in the outpatient setting where ConvP could be evaluated in patients with a higher likelihood of disease progression based on clinical (e.g. age, comorbidities) or other (e.g.
    • CRP, LDH) characteristics.
    • Our data also show that in hospitalized patients testing for the presence of antibodies prior to ConvP should be part of the protocol, and stratifying or even excluding patients based on a positive antibody test will be needed.
    • With the large variety of serological assays that have come available, it is important to carefully validate the assays prior to use and ideally correlate the assay to gold standard virus neutralization assays.
    • Second, ConvP may have an effect that is unrelated to the neutralizing antibodies because therapy with intravenous immunoglobulines or plasma can have diverse anti-inflammatory and immunomodulatory effects as well.
    • However, we considered any such effect unlikely because doses of Ig therapy when used as an immunomodulatory agent are typically at least 10-fold higher than the quantity of immunoglobulins in 300ml plasma.
    • Finally, the recently completed dexamethasone arm of the recovery trial demonstrated an improved overall survival with dexamethasone therapy in patients requiring supplemental oxygen therapy.

    Results from OddPub: We did not find a statement about open data. We also did not find a statement about open code. Researchers are encouraged to share open data when possible (see Nature blog).

    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.

  5. Version published to 10.1101/2020.07.01.20139857v1 on medRxiv