J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp-2021-327200 on 18 August 2021. Downloaded from Letter

patients had experienced SARS-CoV­ -2 mRNA COVID-19 do Table 1 Characteristics of the cohort confirmed by a molecular swab not increase the short-­term risk Demographic features (224.8±103.5 days before the first dose of clinical relapses in Number 324 of vaccination). Overall, 322/324 patients Age (years) 42.7±10.8 (99.4%) underwent both the doses of the Gender (female) 242 (74.7%) with an interval between doses Clinical characteristics of 21.5±4 days. Two patients did not Disease course: RR 303 (93.5%) complete the vaccination schedule: one INTRODUCTION SP 15 (4.6%) because of the evidence of SARS-CoV­ -2 Multiple sclerosis (MS) is a chronic, PP 6 (1.9%) infection after the first dose and the other immune-­mediated disorder of the Disease duration (years) 11.9±8.5 because of the evidence of radiological central nervous system. A novel coro- EDSS Score at the time of vaccination 2.1±1.5 activity without clinical relapses in an navirus, namely SARS-­CoV-2, has been DMTs at the time of vaccination already planned MRI scan, 3 days after the recently responsible for the highly Glatiramer acetate 21 (6.5%) first dose, for which the second vaccine infectious disease referred as COVID- Interferons 52 (16.0%) dose was postponed. In the 2 months 19, rapidly spreading all over the  84 (25.9%) before vaccination, six clinical relapses world. Many vaccines have been devel- Teriflunomide 20 (6.2%) were reported in 6 out of 324 patients oped to control COVID-19 pandemic, Fingolimod 31 (9.6%) (1.9%). In the 2 months after vaccina- including the mRNA vaccines /  37 (11.4%) tion, seven clinical relapses occurred in BioNTech (BNT162b2) and Cladribine 9 (2.8%) 1 7/324 patients (2.2%). The incidence of (mRNA1273). The vaccination of people Ocrelizumab 31 (9.6%) relapses in the 2 months before and after with MS (pwMS) has been recommended Siponimod 1 (0.3%) vaccination was not statistically different by several national and international MS Alemtuzumab 5 (1.5%) (B=0.154, 95% CI −0.948 to 1.288, societies. However, effectiveness and  5 (1.5%) p=0.78). Also, demographical (age, safety of anti-CO­ VID-19 mRNA vaccines Azathioprine 1 (0.3%) gender) and clinical disease characteristics in MS need to be confirmed. The aim of Methotrexate 1 (0.3%) (disease duration, EDSS) had no effect on this study was to evaluate the short-­term No therapy 26 (8.0%) relapses occurrence. Five of the relapsing risk of clinical relapses in pwMS in the Continuous variables are reported as mean±SD. Categorical variables are reported as number (percentage). patients were women. Five relapses were 2 months after the first administration of DMTs, disease-­modifying treatments; EDSS, Expanded Disability monofocal and two were multifocal. The an mRNA COVID-19 vaccine. Status Scale; PP, primary progressive; RR, relapsing remitting; SP, secondary progressive. mean time interval between the first dose of vaccination and the clinical relapse was 44±11.6 days. At the time of vaccination, PATIENTS AND METHODS disease-­modifying treatments at the time three patients were treated with dimethyl Twenty-five­ Italian MS tertiary centres of vaccination. The presence, characteris- fumarate, one with glatiramer acetate, two participated to this prospective, tics and number of relapses in the 60 days with ocrelizumab and one was not treated. self-controlled,­ multicentric obser- after the first administration of the vaccine vational study. In Italy, COVID-19 popu- were recorded. A relapse was defined as lation vaccination started at the end a clinical episode suggestive of demyelin- DISCUSSION of December 2020 and first involved ation developing acutely or subacutely, Vaccines safety in pwMS has been matter 2–4 healthcare professionals. All pwMS, diag- with a duration of at least 24 hours in the of debate. In the current COVID-19 http://jnnp.bmj.com/ nosed according to McDonald’s 2017 absence of fever or infection. The interval pandemic scenario, the availability of criteria, who underwent the first dose between vaccination and clinical relapse mRNA vaccines warrants the urgent of an mRNA COVID-19 vaccine within was calculated. need to define their safety in pwMS. Our January 2021 were recruited from each preliminary analysis demonstrated that the participating centre. All patients received Pfizer/BioNTech BNT162b2 vaccine does Pfizer/BioNTech BNT162b2 vaccine STATISTICAL ANALYSIS not increase the short-­term risk of clinical

according to vaccine availability in Italy. Continuous variables are reported as reactivation in pwMS. Recently, Achiron on October 2, 2021 by guest. Protected copyright. Database lock was planned on 31 March mean±SD, while categorical variables are et al reported in an observational study so that all patients were followed for at reported as count and percentages. To test on 555 pwMS a similar rate of patients least 2 months after the first dose. The the difference between relapses incidence with acute relapse after Pfizer/BioN- following data were collected: (1) sex; in the 2 months before and after vaccina- Tech BNT162b2 vaccine. No increased (2) age and disease duration; (3) disease tion, we fitted a paired negative binomial risk of relapse activity was estimated course (relapsing remitting; secondary model. Demographical and clinical vari- comparing that cohort with a cohort of progressive; primary progressive); (4) ables (age, gender, disease duration and non-vaccinated­ patients evaluated in the disability score (Expanded Disability EDSS) were also included as covariates. same period in the prepandemic era.5 The Status Scale, EDSS); (5) clinical relapses in For all the tests, significance was set at a latter study, however, suffers of the limita- the year before vaccination, with specific p value<0.05. tion of an heterogeneous follow-up­ period regard to the 2 (about 20% of patients with relapses were months immediately preceding vaccina- followed for less than 14 days after immu- tion; (6) MRI activity in the year before RESULTS nisation) which might have lowered the vaccination (new T2 or Gd enhancing— We included 324 pwMS exposed to the number of recorded relapses. Our study Gd+—lesions); (7) previous molecular Pfizer/BioNTech BNT162b2 vaccine. is the first prospective study including a swab confirmed SARS-CoV­ -2 infection; Cohort characteristics are reported in large cohort of patients with MS who were (8) vaccine administration date and (9) table 1. Overall, 28 out of 324 (8.6%) followed, with a self-controlled­ design,

J Neurol Neurosurg Psychiatry Month 2021 Vol 0 No 0 1 J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp-2021-327200 on 18 August 2021. Downloaded from Letter for at least 2 months after the first dose of 13Dipartimento di Scienze Biomediche, Metaboliche e , Idec, Merck, Teva and Bayer; speaker the Pfizer/BioNTech BNT162b2 vaccine. Neuroscienze, Università di Modena e Reggio Emilia, and writing honoraria from Mylan, Teva, Biogen Idec, Modena, Italy Bayer, Genzyme and Merck and travel grants A limit of our study, mainly related to 14Dipartimento di Neuroscienze, Biomedicina e from Teva, Biogen Idec, Sanofi Genzyme, Roche and its real life context, is the lack of MRI Movimento, Università di Verona, Verona, Italy Novartis. MR received honoraria or consultation fees data, which might prevent the detection 15Dipartimento di Neuroscienze, Ospedale San Camillo-­ from Biogen Idec, Sanofi Genzyme, Novartis and Forlanini, Rome, Italy Merck Serono. AL received grants from Fondazione of potential MRI activity in absence of 16 clinical relapses, as well as the short-­term UOC Neurologia, Policlinico Universitario Tor Vergata, Italiana Sclerosi Multipla, Italian Ministry of Health, Rome, Italy Italian Ministry of University and received honoraria or follow-­up. Larger observational studies 17Dipartimento di Neuroscienze e Scienze Riproduttive consultation fees from Biogen, Roche, Merck, Genzyme with longer follow-up­ would be desir- ed Odontostomatologiche, Università degli Studi and Novartis. FB received honoraria for speaking or able. Moreover, due to the low number of Federico II, Naples, Italy consultation fees from Biogen, Roche, Merck Serono, 18 patients with progressive MS in the cohort Dipartimento di Scienze Cliniche e Biologiche Novartis, Sanofi Genzyme and Teva. LL received travel dell’Università di Torino, AOU San Luigi Gonzaga di grant, speaker fees and consultancy from Biogen Idec, (21 out of 324 subjects, 6.5%), no clear Orbassano, Orbassano, Italy Teva, Genzyme, Merck Serono, Novartis, Roche and conclusions can be drawn on the effects 19Centro Sclerosi Multipla, Clinica Neurologica, Almirall. DF has received travel grants and/or speaker/ of Pfizer/BioNTech BNT162b2 vaccina- Ospedale Universitario SS Annunziata, Chieti, Italy advisory board honoraria from Merck, Sanofi Genzyme, 20 tion on disease worsening in progressive Istituto di Tecnologie Avanzate Biomediche (ITAB), Roche, Teva, Binding Site, Biogen and Novartis. RF Dipartimento di Neuroscienze, Imaging e Scienze received honoraria or consultation fees from Roche, MS. Despite these limitations, we think Cliniche, Facolta’ di Medicina e Chirurgia, Universita’ di Novartis, Merck and Sanofi Genzyme. RL received that the results of our study can improve Chieti-­Pescara “G. d’Annunzio”, Chieti, Italy honoraries from Biogen, Merck, Sanofi, Roche and clinical practice driving clinical decisions 21Centro Sclerosi Multipla, Università di Verona, Verona, Novartis for lectures or scientific boards. MM has and support the recommendation to Italy received research grants from ECTRIMS-­MAGNIMS, 22 UK MS Society and Merck; honoraria from EMD promote access of pwMS to COVID-19 Clinica Neurologica, Dipartimento di Medicina e Chirurgia, Università degli Studi di Perugia, Perugia, Serono, Ipsen, Merck, Roche and Sanofi Genzyme and vaccination. Italy consultant fees from Veterans Evaluation Services. MaCl 23Dipartimento di Scienze Mediche di base, received personal compensations for public speaking Massimiliano Di Filippo ‍ ‍ ,1 Cinzia Cordioli,2 Neuroscienze ed Organi di Senso, Università degli Studi from Merck, Biogen, Novartis, Sanofi Genzyme, Almirall, Simona Malucchi,3 Pietro Annovazzi,4 di Bari Aldo Moro, Bari, Italy Roche and and received research grants from Paola Cavalla,5 Valentina Torri Clerici,6 24Ospedale “A. Cardarelli”, Dipartimento Emergenza Merck, Biogen and Novartis. GDL served on scientific Paolo Ragonese ‍ ‍ ,7 Viviana Nociti ‍ ‍ ,8 Accettazione, Neurologia, Centro Regionale per la advisory boards and received speaking honoraria or Marta Radaelli,9 Alice Laroni,10 Fabio Buttari,11 Sclerosi Multipla, Naples, Italy travel grants from Biogen, Merck Serono, Novartis, Lorena Lorefice ‍ ‍ ,12 Diana Ferraro ‍ ‍ ,13 25Centro Dipartimentale diagnosi e cura delle malattie Roche and Sanofi Genzyme. VT participated on advisory Alberto Gajofatto,14 Luca Prosperini ‍ ‍ ,15 demielinizzanti, Dipartimento Testa Collo, ASL3 boards for and received speaker or writing honoraria Roberta Fantozzi,11 Laura Boffa,16 Ospedale P.A. Micone, Genova, Italy and funding for traveling from Biogen, Sanofi Genzyme, 26 Roberta Lanzillo ‍ ‍ ,17 Marcello Moccia ‍ ‍ ,17 Dipartimento di Scienze Mediche e Chirurgiche Merck, Novartis, Roche and Almirall. MaCa has received Marinella Clerico,18 Giovanna De Luca,19 Avanzate, Università degli Studi della Campania Luigi consulting and/or lecture fees and/or travel grants Valentina Tomassini,19,20 Vanvitelli, Naples, Italy from Roche, Biogen Idec, Sanofi Genzyme, Novartis 27 Massimiliano Calabrese,21 Angela Borrelli,22 Unità di Neuroriabilitazione, Ospedale Mons. L. and Merck Serono. AB received funding for traveling Damiano Paolicelli,23 Novarese, Moncrivello, Italy from Almirall. DP received honoraria for consultancy 28 Giorgia Teresa Maniscalco,24 Paola Gazzola,25 Centro Regionale Sclerosi Multipla, ASSL Cagliari, ATS from and/or speaking at Biogen Idec, Merck‐Serono, Antonio Gallo,26 Claudio Solaro,27 Sardegna, Dipartimento di Scienze Mediche e Sanità Almirall, Sanofi‐Aventis, Teva, Novartis and Genzyme. Eleonora Cocco ‍ ‍ ,28 Claudio Gasperini ‍ ‍ ,15 Pubblica, Università di Cagliari, Cagliari, Italy GTM received personal compensation from Serono, 15 Biogen, Novartis, Roche and Teva for public speaking Carla Tortorella ‍ ‍ , On behalf of the RIREMS Correspondence to Prof. Massimiliano Di Filippo, (Rising Researchers in MS) group and advisory boards. PG has received honoraria/ Clinica Neurologica, Dipartimento di Medicina e consultation fees from Novartis, Merck and Sanofi 1Clinica Neurologica, Dipartimento di Medicina e Chirurgia, Università degli Studi di Perugia, Perugia, Genzyme. CS received travel grant and honoraria from IT, University of Perugia, Perugia, Umbria, Italy; ​

Chirurgia, University of Perugia, Perugia, Umbria, Italy Merck, Biogen, Novartis and . EC has received http://jnnp.bmj.com/ 2Centro Sclerosi Multipla, ASST Spedali Civili di Brescia, massimiliano.difilippo@​ ​unipg.it​ consulting and/or lecture fees and/or travel grants from Ospedale di Montichiari, Brescia, Italy Acknowledgements MDF and AB thank Lorenzo Biogen Idec, Sanofi Genzyme, Merck Serono, Novartis 3A.O.U. Centro Sclerosi Multipla, San Luigi Gonzaga, Gaetani for critically reading the manuscript and useful and Roche. CG received fees for speaking and advisory Orbassano, Italy suggestions. CC thanks all the staff members at the boards from Merck, Biogen, Novartis, Teva, Roche, 4U.O.C. Centro Sclerosi Multipla, ASST Valle Olona, ’Centro Sclerosi Multipla, Azienda Ospedaliera Ospedali Almirall, Bayer, Mylan and Sanofi. CT received honoraria Gallarate, Italy Civili – Brescia, IT’ for data collection at their clinical for speaking and travel grants from Biogen, Sanofi 5Centro Sclerosi Multipla e Neurologia 1 D.U, site. Aventis, Merck Serono, Bayer Schering, Teva, Genzyme, Almirall and Novartis. Dipartimento di Neuroscienze e Salute Mentale, Contributors MDF and CT conceived the study. on October 2, 2021 by guest. Protected copyright. Azienda Ospedaliero-­Universitaria Città della Salute e All authors provided clinical data of patients and Patient consent for publication Not required. della Scienza di Torino, Turin, Italy contributed to the writing of the manuscript and 6Centro Sclerosi Multipla, Fondazione I.R.C.C.S. Ethics approval The study was approved by the local approved its final version. MDF, AB and CT prepared the ethics committee (CER Umbria: number 3951/21). Istituto Neurologico Carlo Besta, Dipartimento di draft of the manuscript. Neuroimmunologia e Malattie Neuromuscolari, Milan, Provenance and peer review Not commissioned; Italy Funding The authors have not declared a specific externally peer reviewed. 7Dipartimento di Biomedicina, Neuroscienze e grant for this research from any funding agency in the This article is made freely available for use in Diagnostica Avanzata, Università degli Studi di Palermo, public, commercial or not-­for-­profit sectors. accordance with BMJ’s website terms and conditions Palermo, Italy Competing interests MDF participated on advisory for the duration of the covid-19 pandemic or until 8Centro Sclerosi Multipla, Fondazione Policlinico boards for and received speaker or writing honoraria otherwise determined by BMJ. You may use, download Universitario Agostino Gemelli IRCCS – Università and funding for traveling from Bayer, Biogen Idec, and print the article for any lawful, non-­commercial Cattolica del Sacro Cuore, Rome, Italy Genzyme, Merck, Mylan, Novartis, Roche and Teva. purpose (including text and data mining) provided that 9UOC di Neurologia, ASST Papa Giovanni XXIII, CC received consulting fees for speaking and advisory all copyright notices and trade marks are retained. Bergamo, Italy board from Biogen, Novartis, Merck Serono, Almirall 10 Dipartimento di Neuroscienze, Riabilitazione, and Roche. SM received honoraria from speaking and © Author(s) (or their employer(s)) 2021. No commercial Oftalmologia, Genetica, Maternità e Infanzia Università advisory board from Biogen, Merck Serono, Novartis re-use­ . See rights and permissions. Published by BMJ. di Genova, IRCCS Ospedale Policlinico San Martino, and Sanofi Genzyme. PC participated on advisory Genova, Italy boards for, received speaker or writing honoraria and 11Unità di Neurologia, IRCCS Neuromed, Pozzilli, Italy funding for traveling from Almirall, Biogen, Sanofi 12Centro Regionale Sclerosi Multipla, ASSL Cagliari, ATS Genzyme, Merck-Serono­ , Novartis, Roche and Teva. To cite Di Filippo M, Cordioli C, Malucchi S, et al. J Sardegna, Cagliari, Italy VN has received consulting fees from Novartis, Roche, Neurol Neurosurg Psychiatry Epub ahead of print:

2 J Neurol Neurosurg Psychiatry Month 2021 Vol 0 No 0 J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp-2021-327200 on 18 August 2021. Downloaded from Letter

[please include Day Month Year]. doi:10.1136/jnnp- Roberta Lanzillo http://orcid.​ ​org/0000-​ ​0001-6388-​ ​ report of the Guideline development, Dissemination, 2021-327200 8180 and Implementation Subcommittee of the American Received 21 May 2021 Marcello Moccia http://orcid.​ ​org/0000-​ ​0003-2613-​ ​ Academy of Neurology. Neurology 2019;93:584–94. Accepted 8 August 2021 3090 3 Karussis D, Petrou P. The spectrum of post-­vaccination Eleonora Cocco http://orcid.​ ​org/0000-​ ​0002-3878-​ ​8820 inflammatory CNS demyelinating syndromes. J Neurol Neurosurg Psychiatry 2021;0:1–3. Claudio Gasperini http://orcid.​ ​org/0000-​ ​0002-3959-​ ​ Autoimmun Rev 2014;13:215–24. doi:10.1136/jnnp-2021-327200 4067 4 Lebrun C, Vukusic S. French group for recommendations Carla Tortorella http://orcid.​ ​org/0000-​ ​0001-9037-​ ​7300 ORCID iDs in multiple sclerosis (France4MS) and the Société Massimiliano Di Filippo http://orcid.​ ​org/0000-​ ​0002-​ Francophone de la Sclérose en plaques (SFSEP). 2645-7477​ REFERENCES immunization and multiple sclerosis: recommendations Paolo Ragonese http://orcid.​ ​org/0000-​ ​0003-2516-​ ​ 1 Golob JL, Lugogo N, Lauring AS, et al. SARS-­CoV-2 from the French multiple sclerosis Society. Mult Scler 1567 vaccines: a triumph of and collaboration. JCI Relat Disord 2019;31:173–88. Viviana Nociti http://orcid.​ ​org/0000-​ ​0002-4607-​ ​3948 Insight 2021;6:e149187. 5 Achiron A, Dolev M, Menascu S, et al. COVID-19 Lorena Lorefice http://orcid.​ ​org/0000-​ ​0003-2050-​ ​2908 2 Farez MF, Correale J, Armstrong MJ, et al. Practice vaccination in patients with multiple sclerosis: Diana Ferraro http://orcid.​ ​org/0000-​ ​0003-4818-​ ​3806 guideline update summary: vaccine-­preventable what we have learnt by February 2021. Mult Scler Luca Prosperini http://orcid.​ ​org/0000-​ ​0003-3237-​ ​6267 and immunization in multiple sclerosis: 2021;27:864–70. http://jnnp.bmj.com/ on October 2, 2021 by guest. Protected copyright.

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