B Cell Numbers Predict Humoral and Cellular Response Upon SARS – CoV ‐2 Vaccination Among Patients Treated With Rituximab

  1. Ana‐Luisa Stefanski
  2. Hector Rincon‐Arevalo
  3. Eva Schrezenmeier
  4. Kirsten Karberg
  5. Franziska Szelinski
  6. Jacob Ritter
  7. Bernd Jahrsdörfer
  8. Hubert Schrezenmeier
  9. Carolin Ludwig
  10. Arne Sattler
  11. Katja Kotsch
  12. Yidan Chen
  13. Anne Claußnitzer
  14. Hildrun Haibel
  15. Fabian Proft
  16. Gabriela Guerra
  17. Pawel Durek
  18. Frederik Heinrich
  19. Marta Ferreira‐Gomes
  20. Gerd R. Burmester
  21. Andreas Radbruch
  22. Mir‐Farzin Mashreghi
  23. Andreia C. Lino
  24. Thomas Dörner

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Abstract

Patients with autoimmune inflammatory rheumatic diseases receiving rituximab (RTX) therapy are at higher risk of poor COVID‐19 outcomes and show substantially impaired humoral immune response to anti–SARS–CoV‐2 vaccine. However, the complex relationship between antigen‐specific B cells and T cells and the level of B cell repopulation necessary to achieve anti‐vaccine responses remain largely unknown.

Methods

Antibody responses to SARS–CoV‐2 vaccines and induction of antigen‐specific B and CD4/CD8 T cell subsets were studied in 19 patients with rheumatoid arthritis (RA) or antineutrophil cytoplasmic antibody–associated vasculitis receiving RTX, 12 patients with RA receiving other therapies, and 30 healthy controls after SARS–CoV‐2 vaccination with either messenger RNA or vector‐based vaccines.

Results

A minimum of 10 B cells per microliter (0.4% of lymphocytes) in the peripheral circulation appeared to be required for RTX‐treated patients to mount seroconversion to anti‐S1 IgG upon SARS–CoV‐2 vaccination. RTX‐treated patients who lacked IgG seroconversion showed reduced receptor‐binding domain–positive B cells ( P  = 0.0005), a lower frequency of Tfh‐like cells ( P  = 0.0481), as well as fewer activated CD4 ( P  = 0.0036) and CD8 T cells ( P  = 0.0308) compared to RTX‐treated patients who achieved IgG seroconversion. Functionally relevant B cell depletion resulted in impaired interferon‐γ secretion by spike‐specific CD4 T cells ( P  = 0.0112, r = 0.5342). In contrast, antigen‐specific CD8 T cells were reduced in both RA patients and RTX‐treated patients, independently of IgG formation.

Conclusion

In RTX‐treated patients, a minimum of 10 B cells per microliter in the peripheral circulation is a candidate biomarker for a high likelihood of an appropriate cellular and humoral response after SARS–CoV‐2 vaccination. Mechanistically, the data emphasize the crucial role of costimulatory B cell functions for the proper induction of CD4 responses propagating vaccine‐specific B cell and plasma cell differentiation.

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  1. Version published to 10.1002/art.42060
  2. ScreenIT

    SciScore for 10.1101/2021.07.19.21260803: (What is this?)

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

    Table 1: Rigor

    Ethicsnot detected.
    Sex as a biological variablenot detected.
    Randomizationnot detected.
    Blindingnot detected.
    Power Analysisnot detected.

    Table 2: Resources

    No key resources detected.

    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:
    However, certain patient groups receiving immunosuppressive therapies appear to develop insufficient humoral and cellular responses 18,23-25, but limited data about the underlying limitations is available. Protection through immunization is achieved by an orchestrated immune response between different cellular subsets of innate (APCs) and adaptive immunity, such as B and T cells. Anti-B cell therapies like anti-CD20 antibodies (rituximab, obinutuzumab and ocrelizumab) and BTK inhibitors are associated with poor humoral SARS-CoV-2 vaccination responses, in patients with AIIRD 17-20, multiple sclerosis 26 and CLL 27. Since B cell depletion enhances the risks for poor Covid-19 outcomes 3, but also can reduce anti-SARS-CoV-2 vaccine responses, it is of utmost importance to delineate the level of B cell repopulation necessary to achieve anti-vaccine responses and get insights into the complex relationship between antigen-specific B and T cells. Therefore, our study aimed to investigate humoral and cellular responses in RTX treated patients versus controls. Consistent with previous data 17-19,22, serologic IgG conversion with formation of neutralizing antibodies was significantly lower and delayed in both, RA and even more pronounced in the RTX cohort compared to HC. This finding was closely linked to the availability of peripheral B cells, activated CD4/8 T cells as well as circulating TFH-like cells. Ongoing antigen exposure through mRNA vaccines seems to permit prolonged GC matu...

    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: Please consider improving the rainbow (“jet”) colormap(s) used on pages 18 and 20. At least one figure is not accessible to readers with colorblindness and/or is not true to the data, i.e. not perceptually uniform.

    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.

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  3. Version published to 10.1101/2021.07.19.21260803v1 on medRxiv