Three-dose mRNA-1273 vaccination schedule: sufficient antibody response in majority of immunocompromised hematology patients

  1. Sabine Haggenburg
  2. Quincy Hofsink
  3. Birgit I. Lissenberg-Witte
  4. Annoek E.C. Broers
  5. Jaap A. van Doesum
  6. Rob S. van Binnendijk
  7. Gerco den Hartog
  8. Michel S. Bhoekhan
  9. Nienke J.E. Haverkate
  10. Judith A. Burger
  11. Joey H. Bouhuijs
  12. Gaby P. Smits
  13. Dorine Wouters
  14. Ester M.M. van Leeuwen
  15. Hetty J. Bontkes
  16. Neeltje A. Kootstra
  17. Sonja Zweegman
  18. Arnon P. Kater
  19. Mirjam H.M. Heemskerk
  20. Kaz Groen
  21. Tom van Meerten
  22. Pim G.N.J. Mutsaers
  23. Tim Beaumont
  24. Marit J. van Gils
  25. Abraham Goorhuis
  26. Caroline E. Rutten
  27. Mette D. Hazenberg
  28. Inger S. Nijhof

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Abstract

Importance

In patients with hematologic malignancies, the immunogenicity of the standard 2-dose mRNA-1273 coronavirus disease 19 (COVID-19) vaccination schedule is often insufficient due to underlying disease and current or recent therapy.

Objective

To determine whether a 3 rd mRNA-1273 vaccination raises antibody concentrations in immunocompromised hematology patients to levels obtained in healthy individuals after the standard 2-dose mRNA-1273 vaccination schedule.

Design

Prospective observational cohort study.

Setting

Four academic hospitals in the Netherlands.

Participants

584 evaluable immunocompromised hematology patients, all grouped in predefined cohorts spanning the spectrum of hematologic malignancies.

Exposure

One additional vaccination with mRNA-1273 5 months after completion of the standard 2-dose mRNA-1273 vaccination schedule.

Main Outcomes and Measures

Serum IgG antibodies to spike subunit 1 (S1) antigens prior to and 4 weeks after each vaccination, and pseudovirus neutralization of wildtype, delta and omicron variants in a subgroup of patients.

Results

In immunocompromised hematology patients, a 3 rd mRNA-1273 vaccination led to median S1 IgG concentrations comparable to concentrations obtained by healthy individuals after the 2-dose mRNA-1273 schedule. The rise in S1 IgG concentration after the 3 rd vaccination was most pronounced in patients with a recovering immune system, but potent responses were also observed in patients with persistent immunodeficiencies. Specifically, patients with myeloid malignancies or multiple myeloma, and recipients of autologous or allogeneic hematopoietic cell transplantation (HCT) reached median S1 IgG concentrations similar to those obtained by healthy individuals after a 2-dose schedule. Patients on or shortly after rituximab therapy, CD19-directed chimeric antigen receptor T cell therapy recipients, and chronic lymphocytic leukemia patients on ibrutinib were less or unresponsive to the 3 rd vaccination. In the 27 patients who received cell therapy between the 2 nd and 3 rd vaccination, S1 antibodies were preserved, but a 3 rd mRNA-1273 vaccination did not significantly enhance S1 IgG concentrations except for multiple myeloma patients receiving autologous HCT. A 3 rd vaccination significantly improved neutralization capacity per antibody.

Conclusions and Relevance

The primary schedule for immunocompromised patients with hematologic malignancies should be supplemented with a delayed 3 rd vaccination. B cell lymphoma patients and allogeneic HCT recipients need to be revaccinated after treatment or transplantation.

Trial Registration

EudraCT 2021-001072-41

Key points

Question

Can a 3 rd mRNA-1273 vaccination improve COVID-19 antibody concentrations in immunocompromised hematology patients to levels similar to healthy adults after the standard 2-dose mRNA-1273 schedule?

Findings

In this prospective observational cohort study that included 584 immunocompromised hematology patients, a 3 rd mRNA-1273 vaccination significantly improved SARS-CoV-2 antibody concentrations to levels not significantly different from those obtained by healthy individuals after the standard 2-dose mRNA-1273 vaccination schedule. Pseudovirus neutralization capacity per antibody of wild type virus and variants of concern also significantly improved.

Meaning

The primary COVID-19 vaccination schedule for immunocompromised patients with hematologic malignancies should be supplemented with a delayed 3 rd vaccination.

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  1. ScreenIT

    SciScore for 10.1101/2022.04.08.22273602: (What is this?)

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

    Table 1: Rigor

    EthicsIRB: Study protocols were approved by the Institutional Review Board of the Amsterdam UMC location Free University and participating centers.
    Consent: All patients provided written informed consent prior to study onset.
    Sex as a biological variablenot detected.
    Randomization23,29,31 Seroconversion was defined as obtaining an S1 IgG concentration >10 binding antibody units (BAU)/ml, and an adequate vaccine response as S1 IgG ≥300 BAU/ml, the IgG concentration that met a SARS-CoV-2 wildtype (Wuhan) virus PRNT50 (plaque reduction neutralization titer) of 40 or higher in 2 independent prospective Dutch mRNA-1273 vaccination cohorts.25,26,32,33 Reference antibody levels were extracted from randomly selected age-matched Dutch citizens who had received a 2nd dose of mRNA-1273 14-61 (median 49) days prior to blood sampling (PIENTER cohort12,27).
    Blindingnot detected.
    Power Analysisnot detected.

    Table 2: Resources

    Antibodies
    SentencesResources
    Antibody concentrations and neutralization: Humoral responses against S1, receptor binding domain (RBD) and nucleocapsid (N) antigen domains of SARS-CoV-2 were quantified 28 days after each vaccination as described.
    S1, receptor binding domain (RBD) and nucleocapsid (N)
    suggested: None
    S1 IgG antibody concentrations <300 or ≥300 BAU/ml after 2nd and after the 3rd vaccination were compared with the McNemar test.
    S1 IgG
    suggested: None
    Software and Algorithms
    SentencesResources
    Statistical analyses were performed using the IBM SPSS Statistics for Windows, Version 26.0 (IBM Corp., Armonk, NY) and R for Windows, Version 4.0.3 (The R Foundation for Statistical Computing, Vienna, Austria).
    SPSS
    suggested: (SPSS, RRID:SCR_002865)

    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.

    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.

  2. Version published to 10.1101/2022.04.08.22273602v1 on medRxiv