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Figure.  SARS-CoV-2 IgG by Disease-Modifying Treatments and Association With CD19+ B-Cell Counts and Months Since Anti-CD20 Therapy
SARS-CoV-2 IgG by Disease-Modifying Treatments and Association With CD19+ B-Cell Counts and Months Since Anti-CD20 Therapy

A, SARS-CoV-2 IgG titers at t1 (21-35 days after the second dose) in patients with multiple sclerosis (MS) under treatment with anti-CD20 antibodies, sphingosine-1-phosphate receptor (S1P) modulators, cladribine, teriflunomide, and no therapy. B, Association between months since last anti-CD20 infusion and CD19+ B-cell repopulation at t0 (within 2 weeks prior to first vaccine dose) in patients with MS under treatment with anti-CD20 antibodies. C, Association between months since last anti-CD20 infusion at t0 and SARS-CoV-2 IgG titers at t1 in patients with MS under treatment with anti-CD20 antibodies (3-6 vs 0-3 months: β = 0.78, P = .27; 6-9 vs 0-3 months: β = 1.50, P = .03; >9 vs 0-3 months: β = 2.45, P = .001). D, Association between CD19+ B-cell count at t0 and SARS-CoV-2 IgG titers at t1 in patients with MS under treatment with anti-CD20 antibodies (1-20 vs 0: β = 1.25, P = .007; >20 vs 0: β = 2.54, P < .001).

Table.  Baseline Demographic Characteristics and SARS-CoV-2 IgG Serostatus at t0 and t1 of Patients With MS Included in the Study (Overall and Stratified by DMT)a
Baseline Demographic Characteristics and SARS-CoV-2 IgG Serostatus at t0 and t1 of Patients With MS Included in the Study (Overall and Stratified by DMT)a
1.
Achiron  A, Mandel  M, Dreyer-Alster  S,  et al.  Humoral immune response to COVID-19 mRNA vaccine in patients with multiple sclerosis treated with high-efficacy disease-modifying therapies.   Ther Adv Neurol Disord. 2021;14:17562864211012835. doi:10.1177/17562864211012835PubMedGoogle Scholar
2.
Baden  LR, El Sahly  HM, Essink  B,  et al; COVE Study Group.  Efficacy and safety of the mRNA-1273 SARS-CoV-2 vaccine.   N Engl J Med. 2021;384(5):403-416. doi:10.1056/NEJMoa2035389PubMedGoogle ScholarCrossref
3.
Polack  FP, Thomas  SJ, Kitchin  N,  et al; C4591001 Clinical Trial Group.  Safety and efficacy of the BNT162b2 mRNA Covid-19 vaccine.   N Engl J Med. 2020;383(27):2603-2615. doi:10.1056/NEJMoa2034577PubMedGoogle ScholarCrossref
4.
Maine  GN, Lao  KM, Krishnan  SM,  et al.  Longitudinal characterization of the IgM and IgG humoral response in symptomatic COVID-19 patients using the Abbott Architect.   J Clin Virol. 2020;133:104663. doi:10.1016/j.jcv.2020.104663PubMedGoogle Scholar
5.
Boremalm  M, Sundström  P, Salzer  J.  Discontinuation and dose reduction of rituximab in relapsing-remitting multiple sclerosis.   J Neurol. 2021;268(6):2161-2168. doi:10.1007/s00415-021-10399-8PubMedGoogle ScholarCrossref
6.
Low  JS, Vaqueirinho  D, Mele  F,  et al.  Clonal analysis of immunodominance and cross-reactivity of the CD4 T cell response to SARS-CoV-2.   Science. 2021;372(6548):1336-1341. doi:10.1126/science.abg8985PubMedGoogle ScholarCrossref
Research Letter
September 23, 2021

Association of Disease-Modifying Treatment and Anti-CD20 Infusion Timing With Humoral Response to 2 SARS-CoV-2 Vaccines in Patients With Multiple Sclerosis

Author Affiliations
  • 1Multiple Sclerosis Center, Department of Neurology, Neurocenter of Southern Switzerland (NSI), Regional Hospital of Lugano, Ente Ospedaliero Cantonale, Lugano, Switzerland
  • 2Department of Medicine, Regional Hospital of Lugano, Ente Ospedaliero Cantonale, Lugano, Switzerland
  • 3Faculty of Biomedical Sciences, Università della Svizzera Italiana, Lugano, Switzerland
  • 4University of Geneva, Geneva, Switzerland
  • 5Institute of Laboratory Medicine, Ente Ospedaliero Cantonale, Bellinzona, Switzerland
JAMA Neurol. 2021;78(12):1529-1531. doi:10.1001/jamaneurol.2021.3609

Studies have shown the messenger RNA (mRNA) vaccine against SARS-CoV-2 is safe in multiple sclerosis (MS), but the humoral response to the vaccine was markedly reduced in patients treated with fingolimod and ocrelizumab.1 We aimed to replicate these findings, test other disease-modifying treatments (DMTs), and investigate whether delaying anti-CD20 infusions can potentiate IgG production following vaccination.

Methods

We performed a prospective observational cohort study at the Neurocenter of Southern Switzerland. Inclusion criteria were a diagnosis of MS (using the 2017 McDonald criteria); age older than 18 years; and being scheduled for SARS-CoV-2 mRNA vaccine (mRNA-1273 [Moderna] or BNT162b2 [Pfizer]).2,3 Exclusion criteria were medical treatments influencing response to vaccines other than MS DMTs and a previous symptomatic laboratory-confirmed SARS-CoV-2 infection. Written informed consent was obtained during routine neurological visits and the study was approved by Canton Ticino ethics committee (CETI3863). This report follows the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) guidelines.

Serum samples were collected at t0 (within 2 weeks prior to first vaccine dose) and t1 (21-35 days after the second dose). Quantification of IgG against SARS-CoV-2 spike receptor-binding domain was performed using a chemiluminescence microparticle immunoassay (Abbott; quantification limits, 21-40 000 AU/mL; cutoff for seropositivity = 50 AU/mL).4 CD19+ B cells were measured at t0 using fluorescence-activated cell sorting. DMTs, time since last anti-CD20 infusion, and CD19+ B-cell counts were tested for association with log-transformed SARS-CoV-2 IgG using linear models adjusted by age and sex.

Results

We recruited 120 patients between February 25, 2021, and May 11, 2021, in the following treatment groups: anti-CD20 (n = 58: ocrelizumab = 32, rituximab = 25, ofatumumab = 1), sphingosine-1-phosphate receptor (S1P) modulators (n = 9: fingolimod = 7, ozanimod = 2), cladribine (n = 15), teriflunomide (n = 24), and no therapy (n = 14). All individuals received 2 vaccine doses (median [IQR] time between doses = 28 [28-30] days). Median (IQR) time between t0 and first vaccine dose and between second dose and t1 was 0 (0-0) and 26 (21-32) days, respectively.

The Table shows demographic and baseline SARS-CoV-2 IgG titers. Four patients had positive results at t0 (cladribine, n = 1; anti-CD20, n = 2; untreated, n = 1) and were excluded from following analyses. The percentage of patients remaining seronegative at t1 was 48.2% in the anti-CD20 group, 33.3% in the S1P modulators group, 7.1% in the cladribine group, 0% in the teriflunomide group, and 0% in the no therapy group (Table). As compared with no therapy, anti-CD20 and S1P modulators were associated with lower SARS-CoV-2 IgG (β = −2.19, P < .001 and β = −1.92, P < .001, respectively), whereas differences were not significant for teriflunomide (β = −0.01, P = .98) and cladribine (β = −0.39, P = .44) (Figure, A).

Given the evidence for low-dose rituximab in MS5 and following the example of neuromyelitis optica, we regularly measure CD19+ B and CD19+ CD27+ memory B cells (at least every 3 months) and schedule ocrelizumab and rituximab infusions in stable patients only in case of CD19+ CD27+ repopulation (≥1 cell/uL). Median (IQR) time between last anti-CD20 infusion and first vaccine dose was 7.1 (4.3-9.3) months, with 19 (34.5%) and 15 (27.3%) patients receiving the first dose at 6 to 9 and more than 9 months after last anti-CD20 infusion, respectively. CD19+ B cells started to repopulate at 6 months after last infusion (Figure, B). There was a progressive increase in SARS-CoV-2 IgG with time since last anti-CD20 infusion (Figure, C) and CD19+ B-cell count (Figure, D). Associations were similar when analyzing rituximab and ocrelizumab separately (not shown). No patients had relapses while waiting for vaccination.

Discussion

In this study, the humoral response against SARS-CoV-2 at 1 month after vaccination was appropriate under treatment with cladribine and teriflunomide and diminished/absent under treatment with anti-CD20 therapies and S1P modulators. Delaying anti-CD20 infusions by 3 to 6 months before vaccination could, however, increase the probability of developing appropriate humoral responses, especially in selected clinically and radiologically stable patients. Limitations of the study include the short follow-up (only 1 month after vaccination), the relatively small sample size (especially of S1P modulators and cladribine groups), and the lack of data on additional DMTs. Future studies should aim at investigating antibody dynamics over time, if and how T cell–mediated responses6 after vaccination are influenced by DMTs, and whether these biological measures actually reflect vaccine efficacy in terms of preventing severe SARS-CoV-2 infection.

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Article Information

Accepted for Publication: August 24, 2021.

Published Online: September 23, 2021. doi:10.1001/jamaneurol.2021.3609

Corresponding Author: Claudio Gobbi, MD, Multiple Sclerosis Center, Department of Neurology, Neurocenter of Southern Switzerland (NSI), Ospedale Civico, Via Tesserete 46, 6900 Lugano, Switzerland (claudio.gobbi@eoc.ch).

Author Contributions: Drs Disanto and Gobbi had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. Drs Gobbi and Zecca contributed equally to the manuscript.

Concept and design: Disanto, Gobbi, Zecca.

Acquisition, analysis, or interpretation of data: All authors.

Drafting of the manuscript: Disanto, Gobbi.

Critical revision of the manuscript for important intellectual content: Sacco, Bernasconi, Martinetti, Keller, Gobbi, Zecca.

Statistical analysis: Disanto.

Administrative, technical, or material support: Disanto, Sacco, Zecca.

Supervision: Gobbi, Zecca.

Conflict of Interest Disclosures: Dr Bernasconi received fees for his participation on advisory boards and travel grants from Gilead Sciences, MSD, ViiV Healthcare, AbbVie, and Pfizer. Dr Gobbi received research grants or honoraria for speaking and consulting fees from Almirall, Biogen, Celgene, Merck, Novartis, Roche, Sanofi Genzyme, Teva Pharma. Dr Zecca received research grants or honoraria for speaking and consulting fees from Almirall, Biogen, Celgene, Lilly, Lundbeck, Merck, Novartis, Roche, Sanofi, Teva Pharma. No other disclosures were reported.

Funding/Support: This study was supported by institutional funds of the Neurocenter of Southern Switzerland.

Role of the Funder/Sponsor: The Neurocenter of Southern Switzerland had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

References
1.
Achiron  A, Mandel  M, Dreyer-Alster  S,  et al.  Humoral immune response to COVID-19 mRNA vaccine in patients with multiple sclerosis treated with high-efficacy disease-modifying therapies.   Ther Adv Neurol Disord. 2021;14:17562864211012835. doi:10.1177/17562864211012835PubMedGoogle Scholar
2.
Baden  LR, El Sahly  HM, Essink  B,  et al; COVE Study Group.  Efficacy and safety of the mRNA-1273 SARS-CoV-2 vaccine.   N Engl J Med. 2021;384(5):403-416. doi:10.1056/NEJMoa2035389PubMedGoogle ScholarCrossref
3.
Polack  FP, Thomas  SJ, Kitchin  N,  et al; C4591001 Clinical Trial Group.  Safety and efficacy of the BNT162b2 mRNA Covid-19 vaccine.   N Engl J Med. 2020;383(27):2603-2615. doi:10.1056/NEJMoa2034577PubMedGoogle ScholarCrossref
4.
Maine  GN, Lao  KM, Krishnan  SM,  et al.  Longitudinal characterization of the IgM and IgG humoral response in symptomatic COVID-19 patients using the Abbott Architect.   J Clin Virol. 2020;133:104663. doi:10.1016/j.jcv.2020.104663PubMedGoogle Scholar
5.
Boremalm  M, Sundström  P, Salzer  J.  Discontinuation and dose reduction of rituximab in relapsing-remitting multiple sclerosis.   J Neurol. 2021;268(6):2161-2168. doi:10.1007/s00415-021-10399-8PubMedGoogle ScholarCrossref
6.
Low  JS, Vaqueirinho  D, Mele  F,  et al.  Clonal analysis of immunodominance and cross-reactivity of the CD4 T cell response to SARS-CoV-2.   Science. 2021;372(6548):1336-1341. doi:10.1126/science.abg8985PubMedGoogle ScholarCrossref
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