SARS-CoV-2 mRNA vaccinations fail to elicit humoral and cellular immune responses in patients with multiple sclerosis receiving fingolimod

  1. Lil Meyer-Arndt
  2. Julian Braun
  3. Florent Fauchere
  4. Kanika Vanshylla
  5. Lucie Loyal
  6. Larissa Henze
  7. Beate Kruse
  8. Manuela Dingeldey
  9. Karsten Jürchott
  10. Maike Mangold
  11. Ardit Maraj
  12. Andre Braginets
  13. Chotima Böttcher
  14. Andreas Nitsche
  15. Kathrin de la Rosa
  16. Christoph Ratswohl
  17. Birgit Sawitzki
  18. Pavlo Holenya
  19. Ulf Reimer
  20. Leif E Sander
  21. Florian Klein
  22. Friedemann Paul
  23. Judith Bellmann-Strobl
  24. Andreas Thiel
  25. Claudia Giesecke-Thiel

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Abstract

SARS-CoV-2 mRNA vaccination of healthy individuals is highly immunogenic and protective against severe COVID-19. However, there are limited data on how disease-modifying therapies (DMTs) alter SARS-CoV-2 mRNA vaccine immunogenicity in patients with autoimmune diseases.

Methods

As part of a prospective cohort study, we investigated the induction, stability and boosting of vaccine-specific antibodies, B cells and T cells in patients with multiple sclerosis (MS) on different DMTs after homologous primary, secondary and booster SARS-CoV-2 mRNA vaccinations. Of 126 patients with MS analysed, 105 received either anti-CD20-based B cell depletion (aCD20-BCD), fingolimod, interferon-β, dimethyl fumarate, glatiramer acetate, teriflunomide or natalizumab, and 21 were untreated MS patients for comparison.

Results

In contrast to all other MS patients, and even after booster, most aCD20-BCD- and fingolimod-treated patients showed no to markedly reduced anti-S1 IgG, serum neutralising activity and a lack of receptor binding domain-specific and S2-specific B cells. Patients receiving fingolimod additionally lacked spike-reactive CD4 + T cell responses. The duration of fingolimod treatment, rather than peripheral blood B and T cell counts prior to vaccination, determined whether a humoral immune response was elicited.

Conclusions

The lack of immunogenicity under long-term fingolimod treatment demonstrates that functional immune responses require not only immune cells themselves, but also access of these cells to the site of inoculation and their unimpeded movement. The absence of humoral and T cell responses suggests that fingolimod-treated patients with MS are at risk for severe SARS-CoV-2 infections despite booster vaccinations, which is highly relevant for clinical decision-making and adapted protective measures, particularly considering additional recently approved sphingosine-1-phosphate receptor antagonists for MS treatment.

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  1. Version published to 10.1136/jnnp-2022-329395
  2. ScreenIT

    SciScore for 10.1101/2022.02.06.22270550: (What is this?)

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

    Table 1: Rigor

    EthicsIRB: Participants and ethics: The study was approved by the ethics committee of the Charité – Universitätsmedizin Berlin (EA/152/20) and was conducted in accordance with the World Medical Association’s Declaration of Helsinki of 1964 and its later amendments.
    Consent: Written informed consent was obtained from all participants.
    Sex as a biological variablenot detected.
    Randomizationnot detected.
    Blindingnot detected.
    Power Analysisnot detected.

    Table 2: Resources

    Software and Algorithms
    SentencesResources
    Data collection and statistical analysis: Study data were collected and managed using REDCap electronic data capture tools hosted at the Charité.
    REDCap
    suggested: (REDCap, RRID:SCR_003445)
    Flow cytometry data were analysed using FlowJo 10 (BD)
    FlowJo
    suggested: (FlowJo, RRID:SCR_008520)
    Prism 9 (GraphPad) was used for data plotting and statistical analyses: Fisher’s exact test for seroconversion rate comparison; Kruskal-Wallis test followed by Dunn’s multiple comparisons test for group comparisons; Spearman correlation for correlation testing.
    GraphPad
    suggested: (GraphPad Prism, RRID:SCR_002798)

    Results from OddPub: Thank you for sharing your code.

    Results from LimitationRecognizer: We detected the following sentences addressing limitations in the study:
    A notable limitation, however, for both assays is the skewing of peripheral T cell subsets toward CD8+ T cells in fingolimod-treated patients. As a result, for the same number of cells seeded for stimulation, fewer CD4+ T helper cells are seeded than in all other patient groups, thereby affecting detection limits. Further studies will be required to clarify the discrepancies and guide precautionary measures for these patients. While in aCD20-BCD-treated patients, vaccination efficacy correlated with the time elapsed since last treatment administration and the absolute number of B cells at the time of vaccination, in fingolimod-treated patients, vaccine-induced humoral responses were negatively correlated with overall treatment duration. In MS, treatment suspension is often not feasible as reduced immunomodulation increases the risk of autoimmune flare-ups. Thus, there are currently very few options to improve the pre-conditions for successful vaccination outcomes in these patients, which poses a high risk to them. It remains unclear why a few fingolimod-treated patients mounted (low) humoral and cellular immune responses after secondary vaccination while most others did not. In summary, in striking contrast to all other DMTs, the majority of patients treated with fingolimod appear to be unable to mount specific B and T cell responses to SARS-CoV-2 vaccination. Accordingly, fingolimod-treated patients may require frequent immune check-ups and further means of protection, which...

    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.
    • Thank you for including a protocol registration statement.

    Results from scite Reference Check: We found no unreliable references.

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  3. Version published to 10.1101/2022.02.06.22270550v1 on medRxiv