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Immunogenicity and safety of a fourth COVID-19 vaccination in rituximab-treated patients: an open-label extension study
  1. Daniel Mrak1,
  2. Elisabeth Simader1,
  3. Daniela Sieghart1,
  4. Peter Mandl1,
  5. Helga Radner1,
  6. Thomas Perkmann2,
  7. Helmuth Haslacher2,
  8. Margareta Mayer3,
  9. Maximilian Koblischke3,
  10. Philipp Hofer4,
  11. Lisa Göschl1,
  12. Felix Kartnig1,
  13. Thomas Deimel1,
  14. Andreas Kerschbaumer1,
  15. Thomas Hummel1,5,
  16. Barbara Kornek6,
  17. Renate Thalhammer2,
  18. Karin Stiasny3,
  19. Stefan Winkler7,
  20. Josef S Smolen1,
  21. Judith H Aberle3,
  22. Daniel Aletaha1,
  23. Leonhard X Heinz1,
  24. Michael Bonelli1
  1. 1 Division of Rheumatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria
  2. 2 Department of Laboratory Medicine, Medical University of Vienna, Vienna, Austria
  3. 3 Center for Virology, Medical University of Vienna, Vienna, Austria
  4. 4 Department of Pathology, Medical University of Vienna, Vienna, Austria
  5. 5 2nd Department of Medicine, Lower Austrian Competence Center for Rheumatology, Landesklinikum Stockerau, Stockerau, Lower Austria, Austria
  6. 6 Department of Neurology, Medical University of Vienna, Vienna, Austria
  7. 7 Division of Infectious Diseases and Tropical Medicine, Department of Internal Medicine I, Medical University of Vienna, Vienna, Austria
  1. Correspondence to Dr Michael Bonelli, Division of Rheumatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria; michael.bonelli{at}meduniwien.ac.at

Abstract

Objectives Patients under rituximab therapy are at high risk for a severe COVID-19 disease course. Humoral immune responses to SARS-CoV-2 vaccination are vastly diminished in B-cell-depleted patients, even after a third vaccine dose. However, it remains unclear whether these patients benefit from a fourth vaccination and whether continued rituximab therapy affects antibody development.

Methods In this open-label extension trial, 37 rituximab-treated patients who received a third dose with either a vector or mRNA-based vaccine were vaccinated a fourth time with an mRNA-based vaccine (mRNA-1273 or BNT162b2). Key endpoints included the humoral and cellular immune response as well as safety after a fourth vaccination.

Results The number of patients who seroconverted increased from 12/36 (33%) to 21/36 (58%) following the fourth COVID-19 vaccination. In patients with detectable antibodies to the spike protein’s receptor-binding domain (median: 8.0 binding antibody units (BAU)/mL (quartiles: 0.4; 13.8)), elevated levels were observed after the fourth vaccination (134.0 BAU/mL (quartiles: 25.5; 1026.0)). Seroconversion and antibody increase were strongly diminished in patients who received rituximab treatment between the third and the fourth vaccination. The cellular immune response declined 12 weeks after the third vaccination, but could only be slightly enhanced by a fourth vaccination. No unexpected safety signals were detected, one serious adverse event not related to vaccination occurred.

Conclusions A fourth vaccine dose is immunogenic in a fraction of rituximab-treated patients. Continuation of rituximab treatment reduced humoral immune response, suggesting that rituximab affects a second booster vaccination. It might therefore be considered to postpone rituximab treatment in clinically stable patients.

Trial registration number 2021-002348-57.

  • Rituximab
  • Vaccination
  • Covid-19

Data availability statement

Data are available upon reasonable request. Anonymous patient data are available under specific conditions. Proposals will be reviewed and approved by the sponsor, scientific committee and staff on the basis of scientific merit and absence of competing interests. Once the proposal has been approved, data can be transferred through a secure online platform after the signing of a data access agreement and a confidentiality agreement.

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Data availability statement

Data are available upon reasonable request. Anonymous patient data are available under specific conditions. Proposals will be reviewed and approved by the sponsor, scientific committee and staff on the basis of scientific merit and absence of competing interests. Once the proposal has been approved, data can be transferred through a secure online platform after the signing of a data access agreement and a confidentiality agreement.

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Footnotes

  • Handling editor Gerd-Rüdiger R Burmester

  • DM and ES contributed equally.

  • Correction notice This article has been corrected since it published Onine First. The author equal contributation statement has been added.

  • Contributors All authors contributed to manuscript preparation. MB, DA, DS, DM, and SW contributed to the study design. DM, HR, LXA, ES and DS contributed to data analysis. TP, HH and KS performed antibody measurements. JHH, MM and PH contributed to cellular assays, MB, DA, JSS, DM and LXH contributed to the primary manuscript draft. ES, DM, MB, PM, AK, FK, TH and TD contributed to patient recruitment, RT determined leucocyte subsets. MB acts as guarantor and accepts full resposibility for the work.

  • Funding Provision of vaccines and laboratory testing was provided free of charge by the City of Vienna and the Medical University of Vienna via the Vienna General Hospital. Laboratory testing was supported by the Medical-Scientific fund of the Mayor of the federal capital Vienna to JHA (grant Covid003). Otherwise, there was no specific funding or grant for this research from any funding agency in the public, commercial or not-for-profit sectors. The funders had no role in considering the study design or in the collection, analysis, or interpretation of data, the writing of the report, or the decision to submit the article for publication.

  • Competing interests PM reports speaker fees from AbbVie, Janssen and Novartis and research grants from AbbVie, BMS, Novartis, Janssen, MSD and UCB. MB reports about personal fees from Eli-Lilly, DA received grants and consulting fees from AbbVie, Amgen, Lilly, Merck, Novartis, Pfizer, Roche and Sandoz. JSS reports about grants, consulting and personal fees from AbbVie, Astra-Zeneca, Lilly, Novartis, Amgen, Astro, Bristol-Myers Squibb, Celgene, Celltrion, Chugai, Gilead, ILTOO, Janssen, Merck Sharp & Dohme, Novartis-Sandoz, Pfizer, Roche, Samsung and UCB. DM received support for meeting attendances from Pfizer. HH received grants from Glock Health, BlueSky Immunotherapies and Neutrolis. AK reports about speaker and consulting fees from AbbVie, Amgen, Bristol Myers Squibb, Eli Lilly, Gilead, Janssen, Merck Sharp and Dohme, Novartis and Pfizer. All other authors declare no competing interests.

  • Patient and public involvement Patients and/or the public were not involved in the design, or conduct, or reporting, or dissemination plans of this research.

  • Ethical approval The trial was performed in accordance with Good Clinical Practice guidelines and the Declaration of Helsinki. The trial was approved by the University of Vienna ethics committee in September 2021 (EK#: 1481/2021). All patients provided their written informed consent. All trial visits were conducted in a single centre (Vienna General Hospital).

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.