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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
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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.
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.
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