Transfusing Convalescent Plasma as Post-Exposure Prophylaxis Against Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Infection: A Double-Blinded, Phase 2 Randomized, Controlled Trial

  1. Shmuel Shoham
  2. Evan M Bloch
  3. Arturo Casadevall
  4. Daniel Hanley
  5. Bryan Lau
  6. Kelly Gebo
  7. Edward Cachay
  8. Seble G Kassaye
  9. James H Paxton
  10. Jonathan Gerber
  11. Adam C Levine
  12. Arash Naeim
  13. Judith Currier
  14. Bela Patel
  15. Elizabeth S Allen
  16. Shweta Anjan
  17. Lawrence Appel
  18. Sheriza Baksh
  19. Paul W Blair
  20. Anthony Bowen
  21. Patrick Broderick
  22. Christopher A Caputo
  23. Valerie Cluzet
  24. Marie Elena Cordisco
  25. Daniel Cruser
  26. Stephan Ehrhardt
  27. Donald Forthal
  28. Yuriko Fukuta
  29. Amy L Gawad
  30. Thomas Gniadek
  31. Jean Hammel
  32. Moises A Huaman
  33. Douglas A Jabs
  34. Anne Jedlicka
  35. Nicky Karlen
  36. Sabra Klein
  37. Oliver Laeyendecker
  38. Karen Lane
  39. Nichol McBee
  40. Barry Meisenberg
  41. Christian Merlo
  42. Giselle Mosnaim
  43. Han-Sol Park
  44. Andrew Pekosz
  45. Joann Petrini
  46. William Rausch
  47. David M Shade
  48. Janna R Shapiro
  49. J Robinson Singleton
  50. Catherine Sutcliffe
  51. David L Thomas
  52. Anusha Yarava
  53. Martin Zand
  54. Jonathan M Zenilman
  55. Aaron A R Tobian
  56. David J Sullivan

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Abstract

Background

The efficacy of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) convalescent plasma (CCP) for preventing infection in exposed, uninfected individuals is unknown. CCP might prevent infection when administered before symptoms or laboratory evidence of infection.

Methods

This double-blinded, phase 2 randomized, controlled trial (RCT) compared the efficacy and safety of prophylactic high titer (≥1:320 by Euroimmun ELISA) CCP with standard plasma. Asymptomatic participants aged ≥18 years with close contact exposure to a person with confirmed coronavirus disease 2019 (COVID-19) in the previous 120 hours and negative SARS-CoV-2 test within 24 hours before transfusion were eligible. The primary outcome was new SARS-CoV-2 infection.

Results

In total, 180 participants were enrolled; 87 were assigned to CCP and 93 to control plasma, and 170 transfused at 19 sites across the United States from June 2020 to March 2021. Two were excluded for screening SARS-CoV-2 reverse transcription polymerase chain reaction (RT-PCR) positivity. Of the remaining 168 participants, 12/81 (14.8%) CCP and 13/87 (14.9%) control recipients developed SARS-CoV-2 infection; 6 (7.4%) CCP and 7 (8%) control recipients developed COVID-19 (infection with symptoms). There were no COVID-19-related hospitalizations in CCP and 2 in control recipients. Efficacy by restricted mean infection free time (RMIFT) by 28 days for all SARS-CoV-2 infections (25.3 vs 25.2 days; P = .49) and COVID-19 (26.3 vs 25.9 days; P = .35) was similar for both groups.

Conclusions

Administration of high-titer CCP as post-exposure prophylaxis, although appearing safe, did not prevent SARS-CoV-2 infection.

Clinical Trials Registration

NCT04323800.

Article activity feed

  1. Version published to 10.1093/cid/ciac372
  2. ScreenIT

    SciScore for 10.1101/2021.12.13.21267611: (What is this?)

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

    Table 1: Rigor

    EthicsIRB: Ethical Review and Trial Oversight: Approval was obtained from the Institutional Review Boards at Johns Hopkins University School of Medicine functioning as single IRB for all participating sites.
    Consent: All participants provided written informed consent.
    Sex as a biological variablenot detected.
    RandomizationStudy design and overview: A randomized, double-blind, placebo-controlled clinical trial was conducted from to compare the safety and efficacy of transfusion of CCP (intervention) with SARS-CoV-2 non-immune control plasma.
    Blindingnot detected.
    Power AnalysisThe sample size calculation is provided as supplementary material.

    Table 2: Resources

    Antibodies
    SentencesResources
    Efficacy for preventing SARS-CoV-2 infection and COVID-19 was examined based on donor antibody titer through characterization of donor IgG, including end point titers and area under the curve (AUC) using a standardized ELISA to measure IgG against the spike and receptor binding proteins and anti-SARS-CoV-2 IgG against recombinant S1 domain of the SARS-CoV-2 spike protein (Euroimmun) as previously described15.
    anti-SARS-CoV-2 IgG against recombinant S1
    suggested: None

    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:
    The study had limitations. The logistical challenges were formidable and frequently changed with the evolving pandemic. Enrollment declined precipitously with widespread vaccine availability. Previously vaccinated individuals were ineligible for participation, and guidance to defer vaccination until 90 days after receipt of CCP deterred potential subjects. The enrollment goal of 500 total participants was not achieved. However, conditional power analyses for the primary endpoint of infection suggest that results may not have significantly differed if the trial achieved its target enrollment. In conclusion, this RCT of high titer CCP given to participants exposed to, but not infected with SARS-CoV-2, within 120 hours demonstrated that CCP was safe. This study did not provide evidence of efficacy and conditional power analysis suggests that a larger sample would not have had a different result. Future studies of CCP prophylaxis might consider a higher dose of antibodies with multiple units or use of higher titer as well as consider targeting populations most at risk including the immunocompromised or elderly, and might consider greater emphasis on clinical rather than laboratory outcomes.

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

    IdentifierStatusTitle
    NCT04323800Active, not recruitingConvalescent Plasma to Stem Coronavirus (CSSC-001)

    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.

    Results from scite Reference Check: We found no unreliable references.

    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 10.1101/2021.12.13.21267611v1 on medRxiv