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Introduction
Multiple sclerosis (MS) is a chronic, immune-mediated disorder of the central nervous system. A novel coronavirus, namely SARS-CoV-2, has been recently responsible for the highly infectious disease referred as COVID-19, rapidly spreading all over the world. Many vaccines have been developed to control COVID-19 pandemic, including the mRNA vaccines Pfizer/BioNTech (BNT162b2) and Moderna (mRNA1273).1 The vaccination of people with MS (pwMS) has been recommended by several national and international MS societies. However, effectiveness and safety of anti-COVID-19 mRNA vaccines in MS need to be confirmed. The aim of this study was to evaluate the short-term risk of clinical relapses in pwMS in the 2 months after the first administration of an mRNA COVID-19 vaccine.
Patients and methods
Twenty-five Italian MS tertiary centres participated to this prospective, self-controlled, multicentric observational study. In Italy, COVID-19 population vaccination started at the end of December 2020 and first involved healthcare professionals. All pwMS, diagnosed according to McDonald’s 2017 criteria, who underwent the first dose of an mRNA COVID-19 vaccine within January 2021 were recruited from each participating centre. All patients received Pfizer/BioNTech BNT162b2 vaccine according to vaccine availability in Italy. Database lock was planned on 31 March so that all patients were followed for at least 2 months after the first dose. The following data were collected: (1) sex; (2) age and disease duration; (3) disease course (relapsing remitting; secondary progressive; primary progressive); (4) disability score (Expanded Disability Status Scale, EDSS); (5) clinical relapses in the year before vaccination, with specific regard to the 2
months immediately preceding vaccination; (6) MRI activity in the year before vaccination (new T2 or Gd enhancing—Gd+—lesions); (7) previous molecular swab confirmed SARS-CoV-2 infection; (8) vaccine administration date and (9) disease-modifying treatments at the time of vaccination. The presence, characteristics and number of relapses in the 60 days after the first administration of the vaccine were recorded. A relapse was defined as a clinical episode suggestive of demyelination developing acutely or subacutely, with a duration of at least 24 hours in the absence of fever or infection. The interval between vaccination and clinical relapse was calculated.
Statistical analysis
Continuous variables are reported as mean±SD, while categorical variables are reported as count and percentages. To test the difference between relapses incidence in the 2 months before and after vaccination, we fitted a paired negative binomial model. Demographical and clinical variables (age, gender, disease duration and EDSS) were also included as covariates. For all the tests, significance was set at a p value<0.05.
Results
We included 324 pwMS exposed to the Pfizer/BioNTech BNT162b2 vaccine. Cohort characteristics are reported in table 1. Overall, 28 out of 324 (8.6%) patients had experienced SARS-CoV-2 infection confirmed by a molecular swab (224.8±103.5 days before the first dose of vaccination). Overall, 322/324 patients (99.4%) underwent both the doses of the vaccine with an interval between doses of 21.5±4 days. Two patients did not complete the vaccination schedule: one because of the evidence of SARS-CoV-2 infection after the first dose and the other because of the evidence of radiological activity without clinical relapses in an already planned MRI scan, 3 days after the first dose, for which the second vaccine dose was postponed. In the 2 months before vaccination, six clinical relapses were reported in 6 out of 324 patients (1.9%). In the 2 months after vaccination, seven clinical relapses occurred in 7/324 patients (2.2%). The incidence of relapses in the 2 months before and after vaccination was not statistically different (B=0.154, 95% CI −0.948 to 1.288, p=0.78). Also, demographical (age, gender) and clinical disease characteristics (disease duration, EDSS) had no effect on relapses occurrence. Five of the relapsing patients were women. Five relapses were monofocal and two were multifocal. The mean time interval between the first dose of vaccination and the clinical relapse was 44±11.6 days. At the time of vaccination, three patients were treated with dimethyl fumarate, one with glatiramer acetate, two with ocrelizumab and one was not treated.
Characteristics of the cohort
Discussion
Vaccines safety in pwMS has been matter of debate.2–4 In the current COVID-19 pandemic scenario, the availability of mRNA vaccines warrants the urgent need to define their safety in pwMS. Our preliminary analysis demonstrated that the Pfizer/BioNTech BNT162b2 vaccine does not increase the short-term risk of clinical reactivation in pwMS. Recently, Achiron et al reported in an observational study on 555 pwMS a similar rate of patients with acute relapse after Pfizer/BioNTech BNT162b2 vaccine. No increased risk of relapse activity was estimated comparing that cohort with a cohort of non-vaccinated patients evaluated in the same period in the prepandemic era.5 The latter study, however, suffers of the limitation of an heterogeneous follow-up period (about 20% of patients with relapses were followed for less than 14 days after immunisation) which might have lowered the number of recorded relapses. Our study is the first prospective study including a large cohort of patients with MS who were followed, with a self-controlled design, for at least 2 months after the first dose of the Pfizer/BioNTech BNT162b2 vaccine. A limit of our study, mainly related to its real life context, is the lack of MRI data, which might prevent the detection of potential MRI activity in absence of clinical relapses, as well as the short-term follow-up. Larger observational studies with longer follow-up would be desirable. Moreover, due to the low number of patients with progressive MS in the cohort (21 out of 324 subjects, 6.5%), no clear conclusions can be drawn on the effects of Pfizer/BioNTech BNT162b2 vaccination on disease worsening in progressive MS. Despite these limitations, we think that the results of our study can improve clinical practice driving clinical decisions and support the recommendation to promote access of pwMS to COVID-19 vaccination.
Ethics statements
Patient consent for publication
Ethics approval
The study was approved by the local ethics committee (CER Umbria: number 3951/21).
Acknowledgments
MDF and AB thank Lorenzo Gaetani for critically reading the manuscript and useful suggestions. CC thanks all the staff members at the ‘Centro Sclerosi Multipla, Azienda Ospedaliera Ospedali Civili – Brescia, IT’ for data collection at their clinical site.
Footnotes
Contributors MDF and CT conceived the study. All authors provided clinical data of patients and contributed to the writing of the manuscript and approved its final version. MDF, AB and CT prepared the draft of the manuscript.
Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
Competing interests MDF participated on advisory boards for and received speaker or writing honoraria and funding for traveling from Bayer, Biogen Idec, Genzyme, Merck, Mylan, Novartis, Roche and Teva. CC received consulting fees for speaking and advisory board from Biogen, Novartis, Merck Serono, Almirall and Roche. SM received honoraria from speaking and advisory board from Biogen, Merck Serono, Novartis and Sanofi Genzyme. PC participated on advisory boards for, received speaker or writing honoraria and funding for traveling from Almirall, Biogen, Sanofi Genzyme, Merck-Serono, Novartis, Roche and Teva. VN has received consulting fees from Novartis, Roche, Mylan, Biogen Idec, Merck, Teva and Bayer; speaker and writing honoraria from Mylan, Teva, Biogen Idec, Bayer, Sanofi Genzyme and Merck and travel grants from Teva, Biogen Idec, Sanofi Genzyme, Roche and Novartis. MR received honoraria or consultation fees from Biogen Idec, Sanofi Genzyme, Novartis and Merck Serono. AL received grants from Fondazione Italiana Sclerosi Multipla, Italian Ministry of Health, Italian Ministry of University and received honoraria or consultation fees from Biogen, Roche, Merck, Genzyme and Novartis. FB received honoraria for speaking or consultation fees from Biogen, Roche, Merck Serono, Novartis, Sanofi Genzyme and Teva. LL received travel grant, speaker fees and consultancy from Biogen Idec, Teva, Genzyme, Merck Serono, Novartis, Roche and Almirall. DF has received travel grants and/or speaker/advisory board honoraria from Merck, Sanofi Genzyme, Roche, Teva, Binding Site, Biogen and Novartis. RF received honoraria or consultation fees from Roche, Novartis, Merck and Sanofi Genzyme. RL received honoraries from Biogen, Merck, Sanofi, Roche and Novartis for lectures or scientific boards. MM has received research grants from ECTRIMS-MAGNIMS, UK MS Society and Merck; honoraria from EMD Serono, Ipsen, Merck, Roche and Sanofi Genzyme and consultant fees from Veterans Evaluation Services. MaCl received personal compensations for public speaking from Merck, Biogen, Novartis, Sanofi Genzyme, Almirall, Roche and Viatris and received research grants from Merck, Biogen and Novartis. GDL served on scientific advisory boards and received speaking honoraria or travel grants from Biogen, Merck Serono, Novartis, Roche and Sanofi Genzyme. VT participated on advisory boards for and received speaker or writing honoraria and funding for traveling from Biogen, Sanofi Genzyme, Merck, Novartis, Roche and Almirall. MaCa has received consulting and/or lecture fees and/or travel grants from Roche, Biogen Idec, Sanofi Genzyme, Novartis and Merck Serono. AB received funding for traveling from Almirall. DP received honoraria for consultancy from and/or speaking at Biogen Idec, Merck‐Serono, Almirall, Sanofi‐Aventis, Teva, Novartis and Genzyme. GTM received personal compensation from Serono, Biogen, Novartis, Roche and Teva for public speaking and advisory boards. PG has received honoraria/consultation fees from Novartis, Merck and Sanofi Genzyme. CS received travel grant and honoraria from Merck, Biogen, Novartis and Amgen. EC has received consulting and/or lecture fees and/or travel grants from Biogen Idec, Sanofi Genzyme, Merck Serono, Novartis and Roche. CG received fees for speaking and advisory boards from Merck, Biogen, Novartis, Teva, Roche, Almirall, Bayer, Mylan and Sanofi. CT received honoraria for speaking and travel grants from Biogen, Sanofi Aventis, Merck Serono, Bayer Schering, Teva, Genzyme, Almirall and Novartis.
Provenance and peer review Not commissioned; externally peer reviewed.
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