Immunogenicity and Safety of a Third SARS-CoV-2 Vaccine Dose in Patients With Multiple Sclerosis and Weak Immune Response After COVID-19 Vaccination | Demyelinating Disorders | JAMA Neurology | JAMA Network
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Figure.  Development of Anti–SARS-CoV-2 Spike Receptor-Binding Domain (RBD) IgG Levels in Patients With Multiple Sclerosis Who Were Treated With Anti-CD20 or Fingolimod and Underwent Revaccination
Development of Anti–SARS-CoV-2 Spike Receptor-Binding Domain (RBD) IgG Levels in Patients With Multiple Sclerosis Who Were Treated With Anti-CD20 or Fingolimod and Underwent Revaccination

Reduced immunity was assumed in individuals with IgG levels < 70 arbitrary units (AU; red horizontal line) corresponding to a lower level than found in 99% of healthy vaccinated individuals. S2 indicates antibody sample after second vaccine dose; S3, antibody sample after third vaccine dose.

Table.  Clinical, Demographic, and Vaccination-Specific Variables of Patients With Multiple Sclerosis Who Underwent Revaccination
Clinical, Demographic, and Vaccination-Specific Variables of Patients With Multiple Sclerosis Who Underwent Revaccination
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.
König  M, Lorentzen  AR, Torgauten  HM,  et al.  Humoral immunity to SARS-CoV-2 mRNA vaccination in multiple sclerosis: the relevance of time since last rituximab infusion and first experience from sporadic revaccinations.   J Neurol Neurosurg Psychiatry. 2021;jnnp-2021-327612. doi:10.1136/jnnp-2021-327612PubMedGoogle Scholar
3.
Brill  L, Rechtman  A, Zveik  O,  et al.  Humoral and T-cell response to SARS-CoV-2 vaccination in patients with multiple sclerosis treated with ocrelizumab.   JAMA Neurol. Published online September 23, 2021. doi:10.1001/jamaneurol.2021.3599PubMedGoogle Scholar
4.
Holter  JC, Pischke  SE, de Boer  E,  et al.  Systemic complement activation is associated with respiratory failure in COVID-19 hospitalized patients.   Proc Natl Acad Sci U S A. 2020;117(40):25018-25025. doi:10.1073/pnas.2010540117PubMedGoogle ScholarCrossref
5.
Earle  KA, Ambrosino  DM, Fiore-Gartland  A,  et al.  Evidence for antibody as a protective correlate for COVID-19 vaccines.   Vaccine. 2021;39(32):4423-4428. doi:10.1016/j.vaccine.2021.05.063PubMedGoogle ScholarCrossref
6.
Sormani  MP, De Rossi  N, Schiavetti  I,  et al; Musc-19 Study Group.  Disease-modifying therapies and coronavirus disease 2019 severity in multiple sclerosis.   Ann Neurol. 2021;89(4):780-789. doi:10.1002/ana.26028PubMedGoogle ScholarCrossref
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    Research Letter
    January 24, 2022

    Immunogenicity and Safety of a Third SARS-CoV-2 Vaccine Dose in Patients With Multiple Sclerosis and Weak Immune Response After COVID-19 Vaccination

    Author Affiliations
    • 1Department of Neurology, Oslo University Hospital, Oslo, Norway
    • 2Neuro-SysMed, Department of Neurology, Haukeland University Hospital, Bergen, Norway
    • 3Department of Immunology, Oslo University Hospital, Oslo, Norway
    • 4Department of Neurology, Akershus University Hospital, Oslo, Norway
    JAMA Neurol. 2022;79(3):307-309. doi:10.1001/jamaneurol.2021.5109

    Approximately 80% of all patients with multiple sclerosis (MS) treated with anti-CD20 therapy or fingolimod have weak humoral immune responses after 2 doses of messenger RNA (mRNA) COVID-19 vaccines.1-3 The outcome and safety of a third vaccine dose in this group is largely unknown. We reported results from a study designed to assess the immunogenicity and safety of a third dose of mRNA COVID-19 vaccine in patients with MS who were treated with anti-CD20 therapy or fingolimod.

    Methods

    Patients from 3 university hospitals who were enrolled beginning on March 23, 2021, in an ongoing observational cohort study on immune responses after 2 doses of mRNA vaccines2 were offered a third dose (either BNT162b2 [Pfizer-BioNTech] or mRNA-1273 [Moderna]) from July 7, 2021, based on the following inclusion criteria: (1) signed, electronically obtained informed consent and (2) SARS-CoV-2 spike and receptor-binding domain (RBD) IgG less than 70 arbitrary units (AU) after full vaccination. Exclusion criteria were adverse reactions to previous mRNA vaccination, pregnancy, and ongoing acute infection. Antibodies to full-length spike protein from SARS-CoV-2 and the RBD were measured using an in-house bead-based flow cytometric assay4 in all included patients 3 to 12 weeks after full vaccination and 3 to 5 weeks after revaccination. Postimmunization IgG titers were used as a correlate of protection.5 Reduced immunity was assumed in individuals with IgG less than 70 AU corresponding to a lower level than that found in 99% of healthy vaccinated individuals.2 IgG levels less than 5 AU were defined as no antibody response, whereas IgG levels between 5 and 70 AU were defined as a weak antibody response. Background variables were acquired through a digital questionnaire completed by all patients and from patient journals. Information regarding adverse effects was collected 3 to 5 weeks after revaccination. Information regarding COVID-19 vaccines was extracted from the Norwegian Immunization Registry. This study was approved by the Regional Ethical Committee and the Norwegian Medicines Agency and followed the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) guidelines. Continuous and categorical variables were compared using the Mann-Whitney U test. A 2-sided P value < .05 was considered statistically significant. Correlations were assessed using Spearman ρ. Statistical analyses were performed using SPSS, version 26 (IBM).

    Results

    Of 175 invited patients with MS, 130 (74.2%) met the inclusion criteria. The median (IQR) patient age was 47.5 (40.6-56.0) years, and the study included 97 women (74.6%) and 33 men (25.4%). A total of 100 patients (76.9%) received rituximab, 1 patient (0.8%) received ocrelizumab, and 29 patients (22.3%) received fingolimod. All patients underwent revaccination and antibody testing before October 1, 2021 (Table).

    After full vaccination, mean (SD) levels of anti–SARS-CoV-2 spike RBD IgG titer were as follows: anti-CD20 group, 8.9 (13.9) AU and fingolimod group, 9.2 (12.7) AU. After revaccination, mean (SD) levels of anti–SARS-CoV-2 spike RBD IgG titer increased significantly in both treatment groups to 49.4 (75.7) AU in the anti-CD20 group (P < .001) and to 25.1 (29.6) AU in the fingolimod group (P = .006). The proportion of patients with assumed protective humoral immunity (IgG > 70 AU) after revaccination included 25 of 101 patients (24.8%) given anti-CD20 therapy and 2 of 29 patients (6.9%) treated with fingolimod (Figure). Among those with RBD IgG less than 70 AU, compared with those with RBD IgG greater than 70 AU, higher absolute lymphocyte count (mean [SD], 1262 [584] cells/mm3 vs 1508 [560] cells/mm3; P = .03) and higher CD19 B-cell counts (in patients receiving anti-CD20 therapy: mean [SD], 6 [17] cells/mm3 vs 25 [53] cells/mm3; P = .03) were associated with the development of protective humoral immunity. We found no correlation between antibody responses and time from last anti-CD20 infusion to revaccination (Spearman ρ correlation coefficient, 0.70; P = .50) or the cumulative duration of treatment (Spearman ρ correlation coefficient, −0.17; P = .09).

    Adverse effects were observed in 64 of 101 patients (63.4%) with MS treated with anti-CD20 therapy and in 11 of 29 patients (37.9%) treated with fingolimod, the most common being transient local pain and fatigue (Table). No patients experienced serious adverse effects after revaccination. The mean (SD) absolute lymphocyte count was higher in patients who reported adverse effects (1410 [594] cells/mm3) than in patients who did not report adverse effects (1183 [564] cells/mm3; P = .03).

    Discussion

    The results of this cohort study showed that a third dose of the mRNA COVID-19 vaccine was safe and associated with modestly increased levels of anti–SARS-CoV-2 spike RBD IgG antibodies in patients with reduced protective humoral immunity before reimmunization. A higher absolute lymphocyte count was associated with a better antibody response and more adverse effects, and a higher proportion of patients who were treated with anti-CD20 therapy experienced a better antibody response than patients treated with fingolimod. A 25% increase in the number of patients who experienced seroconversion after revaccination and who were treated with anti-CD20 therapy may be of clinical relevance, as these patients have an approximately 3-fold risk of developing serious COVID-196; therefore, our study results suggest that revaccination of these patients should be considered.

    The primary limitation of this study was that it only included assessments of IgG response as a measure of presumed humoral immunity. It is important to note, however, that antibody levels are not fully predictive of protection against infection and that levels lower than the applied cutoff may also be protective. Furthermore, the protective immune response to SARS-CoV-2 also probably depends on T-cell responses.

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    Article Information

    Accepted for Publication: November 29, 2021.

    Published Online: January 24, 2022. doi:10.1001/jamaneurol.2021.5109

    Corresponding Author: Marton König, MD, PhD, Department of Neurology, Oslo University Hospital, PO Box 4956, Nydalen, N-0424 Oslo, Norway (makoni@ous-hf.no).

    Open Access: This is an open access article distributed under the terms of the CC-BY License. © 2022 König M et al. JAMA Neurology.

    Author Contributions: Dr König had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Drs Lund-Johansen and Nygaard are co–last authors.

    Concept and design: König, Vaage, Lund-Johansen, Nygaard.

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

    Drafting of the manuscript: König, Lund-Johansen.

    Critical revision of the manuscript for important intellectual content: All authors.

    Statistical analysis: König, Tran, Nygaard.

    Obtained funding: Nygaard.

    Administrative, technical, or material support: König, Tran, Holmøy, Vaage, Nygaard.

    Supervision: Nygaard.

    Conflict of Interest Disclosures: Dr König reported receiving speaker honoraria from Novartis, Biogen, and AstraZeneca outside the submitted work. Dr Holmøy reported receiving speaker honoraria from Merck, Biogen, Genzyme, Sanofi, Novartis, Roche, and Bristol Myers Squibb during the conduct of the study. No other disclosures were reported.

    Funding/Support: This study was funded by the Coalition for Epidemic Preparedness Innovations and Oslo University Hospital.

    Role of the Funder/Sponsor: The Coalition for Epidemic Preparedness Innovations and Oslo University Hospital 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 Mathias Herstad Øverås, MD, Oslo University Hospital, Oslo, Norway; Adity Chopra, MD, PhD, Oslo University Hospital; Åslaug Rudjord Lorentzen, MD, PhD, Sørlandet Hospital; Siri Mjaaland, MD, PhD, Norwegian Institute of Public Health, Division of Infection Control, Oslo, Norway; Ingeborg Sundsvalen Aaberge, MD, PhD, Norwegian Institute of Public Health, Division of Infection Control; Kjell-Morten Myhr, MD, PhD, Haukeland University, Bergen, Norway; Stig Wergeland, MD, PhD, Haukeland University; Tone Berge, MD, PhD, Metropolitan University, Oslo, Norway; Hanne Flinstad Harbo, MD, PhD, Oslo University Hospital; Øivind Fredvik Torkildsen, MD, PhD, Haukeland University Hospital; Elisabeth Gulowsen Celius, MD, PhD, Oslo University Hospital; Ludvig Andre Munthe, MD, PhD, Oslo University Hospital; Randi Karlsen, MSc, Oslo University Hospital; Lars Skattebøl, MD, Oslo University Hospital; Einar August Høgestøl, MD, PhD, Oslo University Hospital; Rebecca Cox, MD, PhD, University of Bergen, Bergen, Norway; the Bergen COVID-19 Research Group, and the Coalition for Epidemic Preparedness Innovations for their cooperation and support. No one received financial compensation for their contribution.

    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.
    König  M, Lorentzen  AR, Torgauten  HM,  et al.  Humoral immunity to SARS-CoV-2 mRNA vaccination in multiple sclerosis: the relevance of time since last rituximab infusion and first experience from sporadic revaccinations.   J Neurol Neurosurg Psychiatry. 2021;jnnp-2021-327612. doi:10.1136/jnnp-2021-327612PubMedGoogle Scholar
    3.
    Brill  L, Rechtman  A, Zveik  O,  et al.  Humoral and T-cell response to SARS-CoV-2 vaccination in patients with multiple sclerosis treated with ocrelizumab.   JAMA Neurol. Published online September 23, 2021. doi:10.1001/jamaneurol.2021.3599PubMedGoogle Scholar
    4.
    Holter  JC, Pischke  SE, de Boer  E,  et al.  Systemic complement activation is associated with respiratory failure in COVID-19 hospitalized patients.   Proc Natl Acad Sci U S A. 2020;117(40):25018-25025. doi:10.1073/pnas.2010540117PubMedGoogle ScholarCrossref
    5.
    Earle  KA, Ambrosino  DM, Fiore-Gartland  A,  et al.  Evidence for antibody as a protective correlate for COVID-19 vaccines.   Vaccine. 2021;39(32):4423-4428. doi:10.1016/j.vaccine.2021.05.063PubMedGoogle ScholarCrossref
    6.
    Sormani  MP, De Rossi  N, Schiavetti  I,  et al; Musc-19 Study Group.  Disease-modifying therapies and coronavirus disease 2019 severity in multiple sclerosis.   Ann Neurol. 2021;89(4):780-789. doi:10.1002/ana.26028PubMedGoogle ScholarCrossref
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