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Omicron-Specific Cytotoxic T-Cell Responses After a Third Dose of mRNA COVID-19 Vaccine Among Patients With Multiple Sclerosis Treated With Ocrelizumab

Educational Objective
To identify the key insights or developments described in this article
1 Credit CME
Key Points

Question  Are T-cell responses to the SARS-CoV-2 Omicron variant conserved in anti-CD20–treated patients with multiple sclerosis after COVID-19 messenger RNA vaccination?

Findings  In this cohort study of 20 patients treated with ocrelizumab, Omicron spike-specific CD4 and CD8 T cells were detectable in approximately half of patients 6 months after the second vaccine dose, and cytotoxic T-cell responses increased following the third dose. Frequencies of T cells specific to the Delta and Omicron variants were lower compared with the vaccine strain, both before and after receiving a booster dose.

Meaning  In this study of anti-CD20–treated patients with multiple sclerosis, the vaccine-induced T-cell responses were little affected by the mutations carried by Omicron and might prevent severe COVID-19 infection, and a third vaccine dose improved cytotoxic T-cell responses against Omicron.


Importance  The SARS-CoV-2 variant B.1.1.529 (Omicron) escapes neutralizing antibodies elicited after COVID-19 vaccination, while T-cell responses might be better conserved. It is crucial to assess how a third vaccination modifies these responses, particularly for immunocompromised patients with readily impaired antibody responses.

Objective  To determine T-cell responses to the Omicron spike protein in anti-CD20–treated patients with multiple sclerosis (MS) before and after a third messenger RNA COVID-19 vaccination.

Design, Setting, and Participants  In this prospective cohort study conducted from March 2021 to November 2021 at the University Hospital Geneva, adults with MS receiving anti-CD20 treatment (ocrelizumab) were identified by their treating neurologists and enrolled in the study. A total of 20 patients received their third dose of messenger RNA COVID-19 vaccine and were included in this analysis.

Interventions  Blood sampling before and 1 month after the third vaccine dose.

Main Outcomes and Measures  Quantification of CD4 and CD8 (cytotoxic) T cells specific for the SARS-CoV-2 spike proteins of the vaccine strain as well as the Delta and Omicron variants, comparing frequencies before and after the third vaccine dose.

Results  Of 20 included patients, 11 (55%) were male, and the median (IQR) age was 45.8 (37.8-53.3) years. Spike-specific CD4 and CD8 T-cell memory against all variants were maintained in 9 to 12 patients 6 months after their second vaccination, albeit at lower median frequencies against the Delta and Omicron variants compared with the vaccine strain (CD8 T cells: Delta, 83.0%; 95% CI, 73.6-114.5; Omicron, 78.9%; 95% CI, 59.4-100.0; CD4 T cells: Delta, 72.2%; 95% CI, 67.4-90.5; Omicron, 62.5%; 95% CI, 51.0-89.0). A third dose enhanced the number of responders to all variants (11 to 15 patients) and significantly increased CD8 T-cell responses, but the frequencies of Omicron-specific CD8 T cells remained 71.1% (95% CI, 41.6-96.2) of the responses specific to the vaccine strain.

Conclusions and Relevance  In this cohort study of patients with MS treated with ocrelizumab, there were robust T-cell responses recognizing spike proteins from the Delta and Omicron variants, suggesting that COVID-19 vaccination in patients taking B-cell–depleting drugs may protect them against serious complications from COVID-19 infection. T-cell response rates increased after the third dose, demonstrating the importance of a booster dose for this population.

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Article Information

Accepted for Publication: January 28, 2022.

Published Online: February 25, 2022. doi:10.1001/jamaneurol.2022.0245

Corresponding Author: Christiane S. Eberhardt, MD (christiane.eberhardt@unige.ch), and Arnaud M. Didierlaurent, PhD (arnaud.didierlaurent@unige.ch), Centre Médical Universitaire, rue Michel-Servet 1, 1211 Genève 4, Switzerland.

Author Contributions: Drs Didierlaurent and Eberhardt had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. Drs Madelon and Heikkilä contributed equally to the manuscript.

Study concept and design: Madelon, Heikkilä, Sette, Siegrist, Lalive, Didierlaurent, Eberhardt.

Acquisition, analysis, or interpretation of data: Madelon, Heikkilä, Sabater Royo, Fontannaz, Breville, Lauper, Goldstein, Grifoni, Siegrist, Finckh, Lalive, Didierlaurent, Eberhardt.

Drafting of the manuscript: Madelon, Heikkilä, Breville, Lauper, Goldstein, Finckh, Didierlaurent, Eberhardt.

Critical revision of the manuscript for important intellectual content: Madelon, Heikkilä, Sabater Royo, Fontannaz, Lauper, Grifoni, Sette, Siegrist, Finckh, Lalive, Didierlaurent.

Statistical analysis: Madelon, Heikkilä, Breville, Eberhardt.

Obtained funding: Siegrist, Finckh, Didierlaurent, Eberhardt.

Administrative, technical, or material support: Sabater Royo, Fontannaz, Breville, Lauper, Goldstein, Grifoni, Sette, Siegrist, Lalive.

Study supervision: Madelon, Siegrist, Lalive, Didierlaurent, Eberhardt.

Conflict of Interest Disclosures: Dr Lauper has received personal fees from Pfizer, Celltrion, and Viatris outside the submitted work. Dr Sette is a consultant for Gritstone Bio, Flow Pharma, Arcturus Therapeutics, ImmunoScape, CellCarta, Avalia, Moderna, Fortress, and Repertoire. Dr Didierlaurent has received personal fees from Speranza; personal fees from Roche paid to his institution; and is chairman for the World Health Organization Technical Advisory Group on Emergency Use Listing of COVID-19 vaccines (no personal fees). The La Jolla Institute for Immunology has filed for patent protection for various aspects of T-cell epitope and vaccine design work. No other disclosures were reported.

Funding/Support: This work was supported by the HUG Private Foundation (Drs Eberhardt, Siegrist, and Didierlaurent) and by the Giorgi-Cavaglieri Foundation (Dr Didierlaurent). This work was additionally funded in whole or in part with federal funds from the National Institute of Allergy and Infectious Diseases of the National Institutes of Health under contracts 75N93021C00016 and 75N9301900065 (Dr Sette).

Role of the Funder/Sponsor: The funders 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.

Additional Contributions: We thank Sandra Fernandes Oliveira, Olivia Studer, Sandrine Bastard, and colleagues at the Clinical Research Center, University Hospital of Geneva, Faculty of Medicine, University of Geneva, Geneva, Switzerland, for their involvement in patient recruitment and sample collection; Chantal Tougne, Yves Donati, MSc, Wafae Adouan, and Sophie Coudurier for their contributions to processing the clinical samples and support in experimental work; and Myriam Ventura-Lehnis for her administrative support. None of these contributors were compensated for their work. We thank the team from the flow cytometry core facility for their technical support. We thank all colleagues who have provided support to participant recruitment, sample collection, and experimental work. We are grateful to all volunteers for their participation in the study.

World Health Organization. Classification of Omicron (B.1.1.529): SARS-CoV-2 variant of concern. Accessed December 19, 2021. https://www.who.int/news/item/26-11-2021-classification-of-omicron-(b.1.1.529)-sars-cov-2-variant-of-concern
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AMA CME Accreditation Information

Credit Designation Statement: The American Medical Association designates this Journal-based CME activity activity for a maximum of 1.00  AMA PRA Category 1 Credit(s)™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

Successful completion of this CME activity, which includes participation in the evaluation component, enables the participant to earn up to:

  • 1.00 Medical Knowledge MOC points in the American Board of Internal Medicine's (ABIM) Maintenance of Certification (MOC) program;;
  • 1.00 Self-Assessment points in the American Board of Otolaryngology – Head and Neck Surgery’s (ABOHNS) Continuing Certification program;
  • 1.00 MOC points in the American Board of Pediatrics’ (ABP) Maintenance of Certification (MOC) program;
  • 1.00 Lifelong Learning points in the American Board of Pathology’s (ABPath) Continuing Certification program; and
  • 1.00 CME points in the American Board of Surgery’s (ABS) Continuing Certification program

It is the CME activity provider's responsibility to submit participant completion information to ACCME for the purpose of granting MOC credit.

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