{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,25]],"date-time":"2026-09-25T19:20:11Z","timestamp":1790364011045,"version":"4.1.0"},"reference-count":35,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2022,4,1]],"date-time":"2022-04-01T00:00:00Z","timestamp":1648771200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:sec><jats:title>Background<\/jats:title><jats:p>Immunomodulatory\/immunosuppressive activity of multiple sclerosis (MS) disease modifying therapies (DMTs) might affect immune responses to SARS-CoV-2 exposure or vaccination in patients with MS (PwMS). We evaluated the effect of DMTs on humoral and cell-mediated immune responses to 2 and 3 vaccinations and the longevity of SARS-Cov-2 IgG levels in PwMS.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>522 PwMS and 68 healthy controls vaccinated with BNT162b2-Pfizer mRNA vaccine against SARS-CoV-2, or recovering from COVID-19, were recruited in a nation-wide multi-center study. Blood was collected at 3 time-points: 2-16 weeks and ~6 months post 2<jats:sup>nd<\/jats:sup> vaccination and 1-16 weeks following 3<jats:sup>rd<\/jats:sup> vaccination. Serological responses were measured by quantifying IgG levels against the spike-receptor-binding-domain of SARS-CoV-2, and cellular responses (in a subgroup analysis) by quantifying IFN\u03b3 secretion in blood incubated with COVID-19 spike-antigen.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>75% PwMS were seropositive post 2<jats:sup>nd<\/jats:sup> or 3<jats:sup>rd<\/jats:sup> vaccination. IgG levels decreased by 82% within 6 months from vaccination (p&amp;lt;0.0001), but were boosted 10.3 fold by the 3<jats:sup>rd<\/jats:sup> vaccination (p&amp;lt;0.0001), and 1.8 fold compared to \u22643m post 2<jats:sup>nd<\/jats:sup> vaccination (p=0.025). Patients treated with most DMTs were seropositive post 2<jats:sup>nd<\/jats:sup> and 3<jats:sup>rd<\/jats:sup> vaccinations, however only 38% and 44% of ocrelizumab-treated patients and 54% and 46% of fingolimod-treated patients, respectively, were seropositive. Similarly, in COVID-19-recovered patients only 54% of ocrelizumab-treated, 75% of fingolimod-treated and 67% of cladribine-treated patients were seropositive. A time interval of \u22655 months between ocrelizumab infusion and vaccination was associated with higher IgG levels (p=0.039 post-2<jats:sup>nd<\/jats:sup> vaccination; p=0.036 post-3<jats:sup>rd<\/jats:sup> vaccination), and with higher proportions of seropositive patients. Most fingolimod- and ocrelizumab-treated patients responded similarly to 2<jats:sup>nd<\/jats:sup> and 3<jats:sup>rd<\/jats:sup> vaccination. IFN\u03b3-T-cell responses were detected in 89% and 63% of PwMS post 2<jats:sup>nd<\/jats:sup> and 3<jats:sup>rd<\/jats:sup> vaccination, however in only 25% and 0% of fingolimod-treated patients, while in 100% and 86% of ocrelizumab-treated patients, respectively.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>PwMS treated with most DMTs developed humoral and T-cell responses following 2 and 3 mRNA SARS-CoV-2 vaccinations. Fingolimod- or ocrelizumab-treated patients had diminished humoral responses, and fingolimod compromised the cellular responses, with no improvement after a 3<jats:sup>rd<\/jats:sup> booster. Vaccination following &amp;gt;5 months since ocrelizumab infusion was associated with better sero-positivity. These findings may contribute to the development of treatment-stratified vaccination guidelines for PwMS.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fimmu.2022.868915","type":"journal-article","created":{"date-parts":[[2023,2,6]],"date-time":"2023-02-06T09:14:29Z","timestamp":1675674869000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":37,"title":["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"],"prefix":"10.3389","volume":"13","author":[{"given":"Ron","family":"Milo","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elsebeth","family":"Staun-Ram","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dimitrios","family":"Karussis","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Arnon","family":"Karni","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mark A.","family":"Hellmann","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Erez","family":"Bar-Haim","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ariel","family":"Miller","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"name":"The Israeli Neuroimmunology Study Group on COVID-19 Vaccination in Multiple Sclerosis","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2022,4,1]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"1","DOI":"10.3390\/vaccines9020099","article-title":"Multiple Sclerosis and SARS-CoV-2 Vaccination: Considerations for Immune-Depleting Therapies","volume":"9","author":"Sellner","year":"2021","journal-title":"Vaccines"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1056\/nejmoa2114255","article-title":"Protection of BNT162b2 Vaccine Booster Against Covid-19 in Israel","volume":"385","author":"Bar-On","year":"2021","journal-title":"N Engl J Med"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1056\/nejmoa2110475","article-title":"Safety of the BNT162b2 mRNA Covid-19 Vaccine in a Nationwide Setting","volume":"385","author":"Barda","year":"2021","journal-title":"N Engl J Med"},{"key":"B4","unstructured":"The National Multiple Sclerosis Society"},{"key":"B5","unstructured":""},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1038\/s41591-021-01377-8","article-title":"Neutralizing Antibody Levels are Highly Predictive of Immune Protection From Symptomatic SARS-CoV-2 Infection","volume":"27","author":"Khoury","year":"2021","journal-title":"Nat Med"},{"key":"B7","doi-asserted-by":"publisher","first-page":"39\u201343","DOI":"10.1007\/s00415-021-10663-x","article-title":"Serological Response to SARS-CoV-2 Vaccination in Multiple Sclerosis Patients Treated With Fingolimod or Ocrelizumab: An Initial Real-Life Experience","volume":"269","author":"Guerrieri","year":"2021","journal-title":"J Neurol"},{"key":"B8","doi-asserted-by":"publisher","first-page":"103636","DOI":"10.1016\/j.ebiom.2021.103636","article-title":"Discordant Humoral and T Cell Immune Responses to SARS-CoV-2 Vaccination in People With Multiple Sclerosis on Anti-CD20 Therapy Sachin","volume":"73","author":"Gadani","year":"2021","journal-title":"EBioMedicine"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.1016\/s2665-9913(21)00222-8","article-title":"Antibody Development After COVID-19 Vaccination in Patients With Autoimmune Diseases in the Netherlands: A Substudy of Data From Two Prospective Cohort Studies","volume":"3","author":"Boekel","year":"2021","journal-title":"Lancet Rheumatol"},{"key":"B10","doi-asserted-by":"publisher","first-page":"1237\u201340","DOI":"10.1016\/j.neurol.2021.05.001","article-title":"Impact of Disease-Modifying Treatments on Humoral Response After COVID-19 Vaccination: A Mirror of the Response After SARS-CoV-2 Infection","volume":"177","author":"Bigaut","year":"2021","journal-title":"Rev Neurol (Paris)"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.1001\/jamaneurol.2021.3599","article-title":"Humural and T-Cell Response to SARS-CoV-2 Vaccination in Patients With MS Treated With Ocrelizumab","volume":"23","author":"Brill","year":"2021","journal-title":"JAMA Neurol"},{"key":"B12","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1177\/17562864211012835","article-title":"Humoral Immune Response to COVID-19 mRNA Vaccine in Patients With Multiple Sclerosis Treated With High-Efficacy Disease-Modifying Therapies","volume":"14","author":"Achiron","year":"2021","journal-title":"Ther Adv Neurol Disord"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2021.755333","article-title":"Multiple Sclerosis and SARS-CoV-2: Has the Interplay Started","volume":"12","author":"Bellucci","year":"2021","journal-title":"Front Immunol"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.1111\/ene.15028","article-title":"Safety of the BNT162b2 COVID-19 Vaccine in Multiple Sclerosis (MS): Early Experience From a Tertiary MS Center in Israel","volume":"28","author":"Lotan","year":"2021","journal-title":"Eur J Neurol"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.1177\/13524585211003476","article-title":"COVID-19 Vaccination in Patients With Multiple Sclerosis: What We Have Learnt by February 2021","volume":"27","author":"Achiron","year":"2021","journal-title":"Mult Scler J"},{"key":"B16","doi-asserted-by":"publisher","first-page":"e1104","DOI":"10.1212\/nxi.0000000000001104","article-title":"COVID-19 Vaccination Reactogenicity in Persons With Multiple Sclerosis","volume":"9","author":"Briggs","year":"2022","journal-title":"Neurol Neuroimmunol Neuroinflamm"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.1016\/j.jns.2020.117147","article-title":"COVID-19 in Multiple Sclerosis Patients and Risk Factors for Severe Infection","volume":"418","author":"Chaudhury","year":"2020","journal-title":"J Neurol Sci"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.1007\/s40263-021-00804-1","article-title":"COVID-19 in Patients With Multiple Sclerosis: Associations With Disease-Modifying Therapies","volume":"35","author":"Reder","year":"2021","journal-title":"CNS Drugs"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.1002\/ana.26028","article-title":"Disease-Modifying Therapies and Coronavirus Disease 2019 Severity in Multiple Sclerosis","volume":"89","author":"Sormani","year":"2021","journal-title":"Ann Neurol"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.1016\/j.ebiom.2021.103581","article-title":"Effect of SARS-CoV-2 mRNA Vaccination in MS Patients Treated With Disease Modifying Therapies","volume":"72","author":"Sormani","year":"2021","journal-title":"EBioMedicine"},{"key":"B21","first-page":"e541\u201354","article-title":"Humoral- and T-Cell\u2013Specific Immune Responses to SARS-CoV-2 mRNA Vaccination in Patients With MS Using Different Disease-Modifying Therapies","volume-title":"Neurology","author":"Tortorella","year":"2022"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.7326\/M20-7547","article-title":"Antibody Response After SARS-CoV-2 Infection and Implications for Immunity: A Rapid Living Review","volume":"174","author":"Arkhipova-Jenkins","year":"2021","journal-title":"Ann Intern Med"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(21)01290-3","article-title":"Neutralising Antibody Activity Against SARS-CoV-2 VOCs B.1.617.2 and B.1.351 by BNT162b2 Vaccination","volume":"397","author":"Wall","year":"2021","journal-title":"Lancet"},{"key":"B24","doi-asserted-by":"publisher","first-page":"e84","DOI":"10.1056\/nejmoa2114583","article-title":"Waning Immune Humoral Response to BNT162b2 Covid-19 Vaccine Over 6 Months","volume":"385","author":"Levin","year":"2021","journal-title":"N Engl J Med"},{"key":"B25","doi-asserted-by":"publisher","first-page":"17455065211022262","DOI":"10.1177\/17455065211022262","article-title":"Immune System and COVID-19 by Sex Differences and Age","volume":"17","author":"Ciarambino","year":"2021","journal-title":"Women\u2019s Heal"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2021.633184","article-title":"Antibody Responses in COVID-19: A Review","volume":"12","author":"Chvatal-Medina","year":"2021","journal-title":"Front Immunol"},{"key":"B27","doi-asserted-by":"publisher","first-page":"103251","DOI":"10.1016\/j.msard.2021.103251","article-title":"Humoral Immune Response Following SARS-CoV-2 mRNA Vaccination Concomitant to Anti-CD20 Therapy in Multiple Sclerosis \u2606","volume":"56","author":"Novak","year":"2021","journal-title":"Mult Scler Relat Disord"},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.1007\/s10072-021-05397-7","article-title":"Preliminary Evidence of Blunted Humoral Response to SARS-CoV-2 mRNA Vaccine in Multiple Sclerosis Patients Treated With Ocrelizumab","volume":"42","author":"Gallo","year":"2021","journal-title":"Neurol Sci"},{"key":"B29","doi-asserted-by":"publisher","first-page":"1470","DOI":"10.3390\/vaccines9121470","article-title":"Humoral Immune Response After the Third SARS-CoV-2 mRNA Vaccination in CD20 Depleted People With Multiple Sclerosis","volume":"9","author":"Achtnichts","year":"2021","journal-title":"Vaccines"},{"key":"B30","doi-asserted-by":"publisher","first-page":"34462762","DOI":"10.1016\/j.ebiom.2021.103636","article-title":"Discordant Humoral and T Cell Immune Responses to SARS-CoV-2 Vaccination in People With Multiple Sclerosis on Anti-CD20 Therapy","volume":"73","author":"Gadani","year":"2021","journal-title":"EBioMedicine"},{"key":"B31","doi-asserted-by":"publisher","first-page":"1990","DOI":"10.1038\/s41591-021-01507-2","article-title":"Cellular and Humoral Immune Responses Following SARS-CoV-2 mRNA Vaccination in Patients With Multiple Sclerosis on Anti-CD20 Therapy","volume":"27","author":"Apostolidis","year":"2021","journal-title":"Nat Med"},{"key":"B32","doi-asserted-by":"publisher","first-page":"577788","DOI":"10.1016\/j.jneuroim.2021.577788","article-title":"Humoral and Cellular Immunity in Convalescent COVID-19 People With Multiple Sclerosis Treated With Ofatumumab","volume":"362","author":"Adamec","year":"2022","journal-title":"J Neuroimmunol"},{"key":"B33","doi-asserted-by":"publisher","DOI":"10.1016\/j.msard.2021.102777","article-title":"Development of SARS-CoV-2 IgM and IgG Antibodies in a Relapsing Multiple Sclerosis Patient on Ofatumumab","volume":"49","author":"Flores-Gonzalez","year":"2021","journal-title":"Mult Scler Relat Disord"},{"key":"B34","doi-asserted-by":"publisher","DOI":"10.1056\/nejmc2103916","article-title":"Antibody Persistence Through 6 Months After the Second Dose of mRNA-1273 Vaccine for Covid-19","volume":"384","author":"Doria-Rose","year":"2021","journal-title":"N Engl J Med"},{"key":"B35","doi-asserted-by":"publisher","DOI":"10.7861\/CLINMED.2020-0309","article-title":"Rationale for the Use of Sphingosine Analogues in COVID-19 Patients","volume":"21","author":"Tasat","year":"2021","journal-title":"Clin Med J R Coll Phys London"}],"container-title":["Frontiers in Immunology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2022.868915\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,2,6]],"date-time":"2023-02-06T09:14:34Z","timestamp":1675674874000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2022.868915\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,4,1]]},"references-count":35,"alternative-id":["10.3389\/fimmu.2022.868915"],"URL":"https:\/\/doi.org\/10.3389\/fimmu.2022.868915","relation":{},"ISSN":["1664-3224"],"issn-type":[{"value":"1664-3224","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,4,1]]},"article-number":"868915"}}