Immune dynamics in SARS-CoV-2 experienced immunosuppressed rheumatoid arthritis or multiple sclerosis patients vaccinated with mRNA-1273

Abstract

Background: Patients affected by different types of autoimmune diseases, including common conditions such as Multiple Sclerosis (MS) and Rheumatoid Arthritis (RA), are often treated with immunosuppressants to suppress disease activity. It is not fully understood how the SARS-CoV-2 specific humoral and cellular immunity induced by infection and/or upon vaccination is affected by immunosuppressants.

Methods: The dynamics of cellular immune reactivation upon vaccination of SARS-CoV-2 experienced MS patients treated with the humanized anti-CD20 monoclonal antibody ocrelizumab (OCR) and RA patients treated with methotrexate (MTX) monotherapy were analyzed at great depth via high-dimensional flow cytometry of whole blood samples upon vaccination with the SARS-CoV-2 mRNA-1273 (Moderna) vaccine. Longitudinal B and T cell immune responses were compared to SARS-CoV-2 experienced healthy controls (HC) before and 7-days after the first and second vaccination.

Results: OCR-treated MS patients exhibit a preserved recall response of CD8+ T central memory cells following first vaccination compared to healthy controls and a similar CD4+ circulating T follicular helper 1 and T helper 1 dynamics, whereas humoral and B cell responses were strongly impaired resulting in absence of SARS-CoV-2 specific humoral immunity. MTX treatment significantly delayed antibody levels and B reactivation following the first vaccination, including sustained inhibition of overall reactivation marker dynamics of the responding CD4+ and CD8+ T cells.

Conclusion: Together, these findings indicate that SARS-CoV-2 experienced MS-OCR patients still benefit from vaccination by inducing a broad CD8+ T cell response which can contribute to milder disease outcome. A delayed dynamics of vaccine-induced immunological recall in RA-MTX patients support repeated vaccine strategies to protect against future variants of concern, especially for these patients.

Funding: This research project was supported by ZonMw (The Netherlands Organization for Health Research and Development, #10430072010007), the European Union’s Horizon 2020 research and innovation program under the Marie Skłodowska-Curie grant agreement (#792532 and #860003), the European Commission (SUPPORT-E, #101015756) and by PPOC (#20_21 L2506), the NHMRC Leadership Investigator Grant (#1173871).

Data availability

All raw and processed data presented in this study are available at https://flowrepository.org/id/FR-FCM-Z52K

The following data sets were generated

Article and author information

Author details

  1. Niels JM Verstegen

    Department of Immunopathology, Sanquin, Amsterdam, Netherlands
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-5732-4979
  2. Ruth R Hagen

    Department of Hematopoiesis, Sanquin, Amsterdam, Netherlands
    Competing interests
    No competing interests declared.
  3. Jet van den Dijssel

    Department of Hematopoiesis, Sanquin, Amsterdam, Netherlands
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-4849-0374
  4. Lisan H Kuijper

    Department of Immunopathology, Sanquin, Amsterdam, Netherlands
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-3009-0943
  5. Christine Kreher

    Department of Immunopathology, Sanquin, Amsterdam, Netherlands
    Competing interests
    No competing interests declared.
  6. Thomas Ashhurst

    Sydney Cytometry Core Research Facility, University of Sydney, Sydney, Australia
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-7269-7773
  7. Laura YL Kummer

    Department of Neurology and Neurophysiology, Amsterdam University Medical Centers, Amsterdam, Netherlands
    Competing interests
    No competing interests declared.
  8. Maurice Steenhuis

    Department of Immunopathology, Sanquin, Amsterdam, Netherlands
    Competing interests
    No competing interests declared.
  9. Mariel Duurland

    Department of Immunopathology, Sanquin, Amsterdam, Netherlands
    Competing interests
    No competing interests declared.
  10. Rivka de Jongh

    Department of Immunopathology, Sanquin, Amsterdam, Netherlands
    Competing interests
    No competing interests declared.
  11. Nina de Jong

    Department of Immunopathology, Sanquin, Amsterdam, Netherlands
    Competing interests
    No competing interests declared.
  12. Ellen van der Schoot

    Department of Experimental Immunohematology, Sanquin, Amsterdam, Netherlands
    Competing interests
    No competing interests declared.
  13. Amélie V Bos

    Department of Immunopathology, Sanquin, Amsterdam, Netherlands
    Competing interests
    No competing interests declared.
  14. Erik Mul

    Department of Research Facilities, Sanquin, Amsterdam, Netherlands
    Competing interests
    No competing interests declared.
  15. Katherine Kedzierska

    Department of Microbiology and Immunology,, University of Melbourne, Melbourne, Australia
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-6141-335X
  16. Peter J van Dam

    Department of Neurology and Neurophysiology, Amsterdam University Medical Centers, Amsterdam, Netherlands
    Competing interests
    No competing interests declared.
  17. Eileen W Stalman

    Department of Neurology and Neurophysiology, Amsterdam University Medical Centers, Amsterdam, Netherlands
    Competing interests
    No competing interests declared.
  18. Laura Boekel

    Amsterdam Rheumatology and immunology Center, Reade, Amsterdam, Netherlands
    Competing interests
    No competing interests declared.
  19. Gertjan L Wolbink

    Amsterdam Rheumatology and immunology Center, Reade, Amsterdam, Netherlands
    Competing interests
    No competing interests declared.
  20. Sander W Tas

    Amsterdam Rheumatology and immunology Center, Amsterdam University Medical Centers, Amsterdam, Netherlands
    Competing interests
    No competing interests declared.
  21. Joep Killestein

    Department of Neurology, Amsterdam University Medical Centers, Amsterdam, Netherlands
    Competing interests
    Joep Killestein, has speaking relationships with Merck, Biogen, TEVA, Sanofi, Genzyme, Roche and Novartis. AmsterdamUMC, location VUmc, MS Center Amsterdam has received financial support for research activities from Merck, Celgene, Biogen, GlaxoSmithKline, Immunic, Roche, Teva, Sanofi, Genzyme, and Novartis..
  22. Zoé LE van Kempen

    Department of Neurology, Amsterdam University Medical Centers, Amsterdam, Netherlands
    Competing interests
    No competing interests declared.
  23. Luuk Wieske

    Department of Neurology and Neurophysiology, Amsterdam University Medical Centers, Amsterdam, Netherlands
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-2522-4081
  24. Taco W Kuijpers

    Department of Pediatric Immunology, Amsterdam University Medical Centers, Amsterdam, Netherlands
    Competing interests
    No competing interests declared.
  25. Filip Eftimov

    Department of Neurology and Neurophysiology, Amsterdam University Medical Centers, Amsterdam, Netherlands
    Competing interests
    No competing interests declared.
  26. Theo Rispens

    Department of Immunopathology, Sanquin, Amsterdam, Netherlands
    Competing interests
    No competing interests declared.
  27. Marieke SM van Ham

    Department of Immunopathology, Sanquin, Amsterdam, Netherlands
    Competing interests
    No competing interests declared.
  28. Anja ten Brinke

    Department of Immunopathology, Sanquin, Amsterdam, Netherlands
    For correspondence
    a.tenbrinke@sanquin.nl
    Competing interests
    No competing interests declared.
  29. Carolien E van de Sandt

    Department of Microbiology and Immunology,, University of Melbourne, Melbourne, Australia
    For correspondence
    cvandesandt@unimelb.edu.au
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-4155-7433

Funding

ZonMw (#10430072010007)

  • Taco W Kuijpers
  • Filip Eftimov
  • Theo Rispens

Horizon 2020 Framework Programme (#860003)

  • Taco W Kuijpers
  • Filip Eftimov
  • Theo Rispens
  • Carolien E van de Sandt

European Commission (#101015756)

  • Niels JM Verstegen

Horizon 2020 Framework Programme (#792532)

  • Carolien E van de Sandt

NHMRC (1173871)

  • Joep Killestein

PPOC (#20_21 L2506)

  • Taco W Kuijpers
  • Filip Eftimov
  • Theo Rispens

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Ethics

Human subjects: This study was approved by the medical ethical committee (NL74974.018.20 and EudraCT 2021-001102-30, local METC nummer: 2020_194) and registered at Dutch Trial Register (Trial ID NL8900). Written informed consent was obtained from all study participants when enrolled. Participants were recruited between April 16th 2021 and May 20th 2021 at the MS Center Amsterdam, Amsterdam UMC and the Amsterdam READE Rheumatology and Immunology Center and vaccinated between April 19th 2021 and July 1st 2021 with the mRNA-1273 (Moderna) vaccine at an interval of six weeks, according to the Dutch national vaccination guidelines.

Reviewing Editor

  1. Sarah Sasson, The Kirby Institute UNSW, Australia

Publication history

  1. Received: February 17, 2022
  2. Accepted: July 14, 2022
  3. Accepted Manuscript published: July 15, 2022 (version 1)
  4. Version of Record published: July 29, 2022 (version 2)

Copyright

© 2022, Verstegen et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

Metrics

  • 799
    Page views
  • 271
    Downloads
  • 2
    Citations

Article citation count generated by polling the highest count across the following sources: Crossref, PubMed Central, Scopus.

Download links

A two-part list of links to download the article, or parts of the article, in various formats.

Downloads (link to download the article as PDF)

Open citations (links to open the citations from this article in various online reference manager services)

Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)

  1. Niels JM Verstegen
  2. Ruth R Hagen
  3. Jet van den Dijssel
  4. Lisan H Kuijper
  5. Christine Kreher
  6. Thomas Ashhurst
  7. Laura YL Kummer
  8. Maurice Steenhuis
  9. Mariel Duurland
  10. Rivka de Jongh
  11. Nina de Jong
  12. Ellen van der Schoot
  13. Amélie V Bos
  14. Erik Mul
  15. Katherine Kedzierska
  16. Peter J van Dam
  17. Eileen W Stalman
  18. Laura Boekel
  19. Gertjan L Wolbink
  20. Sander W Tas
  21. Joep Killestein
  22. Zoé LE van Kempen
  23. Luuk Wieske
  24. Taco W Kuijpers
  25. Filip Eftimov
  26. Theo Rispens
  27. Marieke SM van Ham
  28. Anja ten Brinke
  29. Carolien E van de Sandt
  30. on behalf of the T2B! immunity against SARS-CoV-2 study group
(2022)
Immune dynamics in SARS-CoV-2 experienced immunosuppressed rheumatoid arthritis or multiple sclerosis patients vaccinated with mRNA-1273
eLife 11:e77969.
https://doi.org/10.7554/eLife.77969
  1. Further reading

Further reading

    1. Computational and Systems Biology
    2. Immunology and Inflammation
    Anastasia O Smirnova, Anna M Miroshnichenkova ... Alexander Komkov
    Tools and Resources Updated

    High-throughput sequencing of adaptive immune receptor repertoires is a valuable tool for receiving insights in adaptive immunity studies. Several powerful TCR/BCR repertoire reconstruction and analysis methods have been developed in the past decade. However, detecting and correcting the discrepancy between real and experimentally observed lymphocyte clone frequencies are still challenging. Here, we discovered a hallmark anomaly in the ratio between read count and clone count-based frequencies of non-functional clonotypes in multiplex PCR-based immune repertoires. Calculating this anomaly, we formulated a quantitative measure of V- and J-genes frequency bias driven by multiplex PCR during library preparation called Over Amplification Rate (OAR). Based on the OAR concept, we developed an original software for multiplex PCR-specific bias evaluation and correction named iROAR: immune Repertoire Over Amplification Removal (https://github.com/smiranast/iROAR). The iROAR algorithm was successfully tested on previously published TCR repertoires obtained using both 5’ RACE (Rapid Amplification of cDNA Ends)-based and multiplex PCR-based approaches and compared with a biological spike-in-based method for PCR bias evaluation. The developed approach can increase the accuracy and consistency of repertoires reconstructed by different methods making them more applicable for comparative analysis.

    1. Cell Biology
    2. Immunology and Inflammation
    Ana J Caetano, Yushi Redhead ... Paul T Sharpe
    Research Article Updated

    The interplay among different cells in a tissue is essential for maintaining homeostasis. Although disease states have been traditionally attributed to individual cell types, increasing evidence and new therapeutic options have demonstrated the primary role of multicellular functions to understand health and disease, opening new avenues to understand pathogenesis and develop new treatment strategies. We recently described the cellular composition and dynamics of the human oral mucosa; however, the spatial arrangement of cells is needed to better understand a morphologically complex tissue. Here, we link single-cell RNA sequencing, spatial transcriptomics, and high-resolution multiplex fluorescence in situ hybridisation to characterise human oral mucosa in health and oral chronic inflammatory disease. We deconvolved expression for resolution enhancement of spatial transcriptomic data and defined highly specialised epithelial and stromal compartments describing location-specific immune programs. Furthermore, we spatially mapped a rare pathogenic fibroblast population localised in a highly immunogenic region, responsible for lymphocyte recruitment through CXCL8 and CXCL10 and with a possible role in pathological angiogenesis through ALOX5AP. Collectively, our study provides a comprehensive reference for the study of oral chronic disease pathogenesis.