BACKGROUND: Rituximab (RTX) and ocrelizumab (OCR), B cell-depleting therapy targeting CD20 molecules, affect the humoral immune response after vaccination. How these therapies influence T-cell-mediated immune response against SARS-CoV-2 after immunization remains unclear. We aimed to evaluate the humoral and cellular immune response to the COVID-19 vaccine in a cohort of patients with multiple sclerosis (MS), neuromyelitis optica spectrum disorders (NMOSD), and myasthenia gravis (MG). METHODS: Patients with MS (83), NMOSD (19), or MG (7) undergoing RTX (n=47) or OCR (n=62) treatment were vaccinated twice with the mRNA BNT162b2 vaccine. Antibodies were quantified using the SARS-CoV-2 IgG chemiluminescence immunoassay, targeting the spike protein. SARS-CoV-2-specific T cell responses were quantified by interferon γ release assays (IGRA). The responses were evaluated at two different time points (4-8 weeks and 16-20 weeks following the 2nd dose of the vaccine). Immunocompetent vaccinated individuals (n=41) were included as controls. RESULTS: Almost all immunocompetent controls developed antibodies against the SARS-CoV-2 trimeric spike protein, but only 34.09% of the patients, without a COVID-19 history and undergoing anti-CD20 treatment (via RTX or OCR), seroconverted. This antibody response was higher in patients with intervals of longer than 3 weeks between vaccinations. The duration of therapy was significantly shorter in seroconverted patients (median 24 months), than in the non-seroconverted group. There was no correlation between circulating B cells and the levels of antibodies. Even patients with a low proportion of circulating CD19+ B cells (<1%, 71 patients) had detectable SARS-CoV-2 specific antibody responses. SARS-CoV-2 specific T cell response measured by released interferon γ was detected in 94.39% of the patients, independently of a humoral immune response. CONCLUSION: The majority of MS, MG, and NMOSD patients developed a SARS-CoV-2-specific T cell response. The data suggest that vaccination can induce SARS-CoV-2-specific antibodies in a portion of anti-CD20 treated patients. The seroconversion rate was higher in OCR-treated patients compared to those on RTX. The response represented by levels of antibodies was better in individuals, with intervals of longer than 3 weeks between vaccinations.

2nd Department of Neurology Faculty of Medicine Comenius University Bratislava Slovakia

Department of Neurology and Centre of Clinical Neuroscience 1st Faculty of Medicine Charles University and General University Hospital Prague Prague Czechia

Institute of Biophysics and Informatics of the 1st Faculty of Medicine Charles University Prague Prague Czechia

Institute of Immunology and Microbiology 1st Faculty of Medicine Charles University and General University Hospital Prague Prague Czechia

Laboratory of Clinical Immunology and Allergology Institute of Clinical Biochemistry and Laboratory Diagnostics 1st Faculty of Medicine Charles University and General University Hospital Prague Prague Czechia

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Graf J, Mares J, Barnett M, Aktas O, Albrecht P, Zamvil SS, et al. . Targeting b cells to modify MS, NMOSD, and MOGAD: part 2. Neurol Neuroimmunol Neuroinflamm (2021) 8(1). doi: 10.1212/NXI.0000000000000918 PubMed DOI PMC

Landon-Cardinal O, Friedman D, Guiguet M, Laforet P, Heming N, Salort-Campana E, et al. . Efficacy of rituximab in refractory generalized anti-AChR myasthenia gravis. J Neuromuscul Dis (2018) 5(2):241–9. doi: 10.3233/JND-180300 PubMed DOI

Jakubikova M, Tyblova M, Tesar A, Horakova M, Vlazna D, Rysankova I, et al. . Predictive factors for a severe course of COVID-19 infection in myasthenia gravis patients with an overall impact on myasthenic outcome status and survival. Eur J Neurol (2021) 28(10):3418–25. doi: 10.1111/ene.14951 PubMed DOI PMC

Srmani MP, Palvetti M, Labauge P, Schiavetti I, Zephir H, Carmisciano L, et al. . DMTs and covid-19 severity in MS: a pooled analysis from Italy and France. Ann Clin Transl Neurol (2021) 8(8):1738–44. doi: 10.1002/acn3.51408 PubMed DOI PMC

Stastna D, Menkyova I, Drahota J, Mazouchova A, Adamkova J, Ampapa R, et al. . Multiple sclerosis, neuromyelitis optica spectrum disorder and COVID-19: a pandemic year in czechia. Mult Scler Relat Disord (2021) 54:103104. doi: 10.1016/j.msard.2021.103104 PubMed DOI PMC

Damato V, Spagni G, Monte G, Scandiffio L, Cavalcante P, Zampetti N, et al. . Immunological response after SARS-CoV-2 infection and mRNA vaccines in patients with myasthenia gravis treated with rituximab. Neuromuscul Disord (2023) 33(3):288–94. doi: 10.1016/j.nmd.2023.02.005 PubMed DOI PMC

Achiron A, Mandel M, Dreyer-Alster S, Harari G, Magalashvili D, Sonis P, 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: 10.1177/17562864211012835 PubMed DOI PMC

Bigaut K, Kremer L, Fleury M, Lanotte L, Collongues N, de Seze J. Impact of disease-modifying treatments on humoral response after COVID-19 vaccination: a mirror of the response after SARS-CoV-2 infection. Rev Neurol (Paris) (2021) 177(10):1237–40. doi: 10.1016/j.neurol.2021.05.001 PubMed DOI PMC

Gadani SP, Reyes-Mantilla M, Jank L, Harris S, Douglas M, Smith MD, et al. . Discordant humoral and T cell immune responses to SARS-CoV-2 vaccination in people with multiple sclerosis on anti-CD20 therapy. medRxiv (2021) 2021.08.23.21262472. doi: 10.1101/2021.08.23.21262472 PubMed DOI PMC

Louapre C, Ibrahim M, Maillart E, Abdi B, Papeix C, Stankoff B, et al. . Anti-CD20 therapies decrease humoral immune response to SARS-CoV-2 in patients with multiple sclerosis or neuromyelitis optica spectrum disorders. J Neurol Neurosurg Psychiatry (2022) 93(1):24–31. doi: 10.1136/jnnp-2021-326904 PubMed DOI

Milo R, Staun-Ram E, Karussis D, Karni A, Hellmann MA, Bar-Haim E, et al. . Humoral and cellular immune responses to SARS-CoV-2 mRNA vaccination in patients with multiple sclerosis: an Israeli multi-center experience following 3 vaccine doses. Front Immunol (2022) 13:868915. doi: 10.3389/fimmu.2022.868915 PubMed DOI PMC

Apostolidis SA, Kakara M, Painter MM, Goel RR, Mathew D, Lenzi K, et al. . Cellular and humoral immune responses following SARS-CoV-2 mRNA vaccination in patients with multiple sclerosis on anti-CD20 therapy. Nat Med (2021) 27(11):1990–2001. doi: 10.1038/s41591-021-01507-2 PubMed DOI PMC

Katz Sand I, Gnjatic S, Krammer F, Tuballes K, Carreno JM, Satyanarayan S, et al. . Evaluation of immunological responses to third COVID-19 vaccine among people treated with sphingosine receptor-1 modulators and anti-CD20 therapy. Mult Scler Relat Disord (2022) 70:104486. doi: 10.1016/j.msard.2022.104486 PubMed DOI PMC

Iannetta M, Landi D, Cola G, Campogiani L, Malagnino V, Teti E, et al. . B- and T-cell responses after SARS-CoV-2 vaccination in patients with multiple sclerosis receiving disease modifying therapies: immunological patterns and clinical implications. Front Immunol (2022) 12:796482. doi: 10.3389/fimmu.2021.796482 PubMed DOI PMC

Rydyznski Moderbacher C, Ramirez SI, Dan JM, Grifoni A, Hastie KM, Weiskopf D, et al. . Antigen-specific adaptive immunity to SARS-CoV-2 in acute COVID-19 and associations with age and disease severity. Cell (2020) 183(4):996–1012 e19. doi: 10.1016/j.cell.2020.09.038 PubMed DOI PMC

Dan JM, Mateus J, Kato Y, Hastie KM, Yu ED, Faliti CE, et al. . Immunological memory to SARS-CoV-2 assessed for up to 8 months after infection. Science (2021) 371(6529). doi: 10.1126/science.abf4063 PubMed DOI PMC

Levin EG, Lustig Y, Cohen C, Fluss R, Indenbaum V, Amit S, et al. . Waning immune humoral response to BNT162b2 covid-19 vaccine over 6 months. N Engl J Med (2021) 385(24):e84. doi: 10.1056/NEJMoa2114583 PubMed DOI PMC

Yang WH, Dionne M, Kyle M, Aggarwal N, Li P, Madariaga M, et al. . Long-term immunogenicity of an AS03-adjuvanted influenza A(H1N1)pdm09 vaccine in young and elderly adults: an observer-blind, randomized trial. Vaccine (2013) 31(40):4389–97. doi: 10.1016/j.vaccine.2013.07.007 PubMed DOI PMC

Disanto G, Sacco R, Bernasconi E, Martinetti G, Keller F, Gobbi C, et al. . Association of disease-modifying treatment and anti-CD20 infusion timing with humoral response to 2 SARS-CoV-2 vaccines in patients with multiple sclerosis. JAMA Neurol (2021) 78(12):1529–31. doi: 10.1001/jamaneurol.2021.3609 PubMed DOI PMC

Gingele S, Jacobus TL, Konen FF, Hümmert MW, Sühs KW, Schwenkenbecher P, et al. . Ocrelizumab depletes CD20+ T cells in multiple sclerosis patients. Cells (2018) 8(1):12. doi: 10.3390/cells8010012 PubMed DOI PMC

von Essen MR, Ammitzbøll C, Hansen RH, Petersen ERS, McWilliam O, Marquart HV, et al. . Proinflammatory CD20+ T cells in the pathogenesis of multiple sclerosis. Brain (2019) 142(1):120–32. doi: 10.1093/brain/awy301 PubMed DOI

Wilk E, Witte T, Marquardt N, Horvath T, Kalippke K, Scholz K, et al. . Depletion of functionally active CD20+ T cells by rituximab treatment. Arthritis Rheumatol (2009) 60(12):3563–71. doi: 10.1002/art.24998 PubMed DOI

Fischer L, Gerstel PF, Poncet A, Siegrist CA, Laffitte E, Gabay C, et al. . Pneumococcal polysaccharide vaccination in adults undergoing immunosuppressive treatment for inflammatory diseases–a longitudinal study. Arthritis Res Ther (2015) 17(1):151. doi: 10.1186/s13075-015-0663-9 PubMed DOI PMC

Reyes-Leiva D, López-Contreras J, Moga E, Pla-Juncà F, Lynton-Pons E, Rojas-Garcia R, et al. . Immune response and safety of SARS-CoV-2 mRNA-1273 vaccine in patients with myasthenia gravis. Neurol Neuroimmunol Neuroinflamm (2022) 9(4):e200002. doi: 10.1212/NXI.0000000000200002 PubMed DOI PMC

Furer V, Eviatar T, Zisman D, Peleg H, Paran D, Levartovsky D, et al. . Immunogenicity and safety of the BNT162b2 mRNA COVID-19 vaccine in adult patients with autoimmune inflammatory rheumatic diseases and in the general population: a multicentre study. Ann Rheum Dis (2021) 80(10):1330–8. doi: 10.1136/annrheumdis-2021-220647 PubMed DOI

Marino M, Basile U, Spagni G, Napodano C, Iorio R, Gulli F, et al. . Long-lasting rituximab-induced reduction of specific-but not total-IgG4 in MuSK-positive myasthenia gravis. Front Immunol (2020) 11:613. doi: 10.3389/fimmu.2020.00613 PubMed DOI PMC

Stastna D, Menkyova I, Drahota J, Hrnciarova T, Kubala Havrdova E, Vachova M, et al. . To be or not to be vaccinated: the risk of MS or NMOSD relapse after COVID-19 vaccination and infection. Mult Scler Relat Disord (2022) 65:104014. doi: 10.1016/j.msard.2022.104014 PubMed DOI PMC

COVID-19 vaccination and relapse activity: A nationwide cohort study of patients with multiple sclerosis in Denmark