Additional heterologous versus homologous booster vaccination in immunosuppressed patients without SARS-CoV-2 antibody seroconversion after primary mRNA vaccination: a randomised controlled trial

  1. Michael Bonelli
  2. Daniel Mrak
  3. Selma Tobudic
  4. Daniela Sieghart
  5. Maximilian Koblischke
  6. Peter Mandl
  7. Barbara Kornek
  8. Elisabeth Simader
  9. Helga Radner
  10. Thomas Perkmann
  11. Helmuth Haslacher
  12. Margareta Mayer
  13. Philipp Hofer
  14. Kurt Redlich
  15. Emma Husar-Memmer
  16. Ruth Fritsch-Stork
  17. Renate Thalhammer
  18. Karin Stiasny
  19. Stefan Winkler
  20. Josef S Smolen
  21. Judith H Aberle
  22. Markus Zeitlinger
  23. Leonhard X Heinz
  24. Daniel Aletaha

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Abstract

SARS‐CoV‐2-induced COVID-19 has led to exponentially rising mortality, particularly in immunosuppressed patients, who inadequately respond to conventional COVID-19 vaccination.

Methods

In this blinded randomised clinical trial, we compare the efficacy and safety of an additional booster vaccination with a vector versus mRNA vaccine in non-seroconverted patients. We assigned 60 patients under rituximab treatment, who did not seroconvert after their primary mRNA vaccination with either BNT162b2 (Pfizer–BioNTech) or mRNA-1273 (Moderna), to receive a third dose, either using the same mRNA or the vector vaccine ChAdOx1 nCoV-19 (Oxford–AstraZeneca). Patients were stratified according to the presence of peripheral B cells. The primary efficacy endpoint was the difference in the SARS-CoV-2 antibody seroconversion rate between vector (heterologous) and mRNA (homologous) vaccinated patients by week 4. Key secondary endpoints included the overall seroconversion and cellular immune response; safety was assessed at week 1 and week 4.

Results

Seroconversion rates at week 4 were comparable between vector (6/27 patients, 22%) and mRNA (9/28, 32%) vaccines (p=0.6). Overall, 27% of patients seroconverted; specific T cell responses were observed in 20/20 (100%) vector versus 13/16 (81%) mRNA vaccinated patients. Newly induced humoral and/or cellular responses occurred in 9/11 (82%) patients. 3/37 (8%) of patients without and 12/18 (67%) of the patients with detectable peripheral B cells seroconverted. No serious adverse events, related to immunisation, were observed.

Conclusions

This enhanced humoral and/or cellular immune response supports an additional booster vaccination in non-seroconverted patients irrespective of a heterologous or homologous vaccination regimen.

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  1. Version published to 10.1136/annrheumdis-2021-221558
  2. ScreenIT

    SciScore for 10.1101/2021.09.05.21263125: (What is this?)

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

    Table 1: Rigor

    EthicsIACUC: The study protocol and all relevant documents were approved by the competent authorities and the local ethical committee (vote number 1481/2021) of the Medical University of Vienna.
    Consent: All patients provided their written informed consent.
    Sex as a biological variablenot detected.
    RandomizationTRIAL DESIGN & POPULATION: In this prospective patient and efficacy (laboratory) blinded randomized controlled trial (EudraCT: 2021-002348-57), adults (≥ 18
    BlindingAll patients were blinded throughout visit four, mainly to allow objectivity in safety assessment of the two strategies; blinding of vaccines was ensured by using pre-arranged dose aliquots in syringes without reference to the type used.
    Power AnalysisBased on a Chi-squared test comparing vector versus mRNA vaccine, this number of patients would allow to achieve at least 80% power at a minimal detectable difference of 28% (5% of responders in one group versus 33% in the other).

    Table 2: Resources

    Antibodies
    SentencesResources
    Secondary endpoints included seroconversion rate and SARS-CoV-2 antibody levels at week 4 overall and stratified for patients with and without detectable peripheral B-cells as well as cellular immune response defined by T lymphocyte restimulation potential before and one week after vaccination.
    SARS-CoV-2
    suggested: None
    Software and Algorithms
    SentencesResources
    Spots were counted using a Bio-Sys Bioreader 5000 Pro-S/BR177 and Bioreader software generation 10.
    Bioreader
    suggested: None
    GraphPad Prism (version 9.1.0) was used for the graphical presentation of the data.
    GraphPad Prism
    suggested: (GraphPad Prism, RRID:SCR_002798)
    “R” version 4.0.3 (R Development Core Team. Vienna, Austria) was used for the entire statistical analysis.
    R Development Core
    suggested: (R Project for Statistical Computing, RRID:SCR_001905)

    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:
    One limitation of the trial is the absence of a placebo control, which was considered unethical in this high-risk population. While the small sample size precluded delivering ultimate statistical evidence concerning the clinical question of differences in immune responses to booster vaccination with homologous versus heterologous products, the important result of our study is that a third booster vaccination is effective in inducing an immune response in these refractory patients. Since we cannot generalize these data to the wider population of non-responders to COVID-19 vaccines, i.e. beyond immunosuppressed patients, broader population-based programs are needed to evaluate the impact of an additional booster vaccination in non-responding healthy individuals. It is important to note, that it still needs to be determined how humoral and cellular immune responses (or their absence) relate to protection against clinical infection with SARS-CoV-2. Our data show that a cellular and/or humoral immune response can be achieved upon a third COVID-19 vaccination in most of the patients who initially developed neither a humoral nor a cellular immune response. The efficacy data together with the safety data seen in our trial provide a favorable risk/benefit ratio and support the implementation of a third vaccination for non-seroconverted high-risk autoimmune disease patients treated with B-cell-depleting agents. This might be a viable way to protect this group of patients from more dire...

    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.

  3. Version published to 10.1101/2021.09.05.21263125v1 on medRxiv