COVID-19 Vaccines and Attributable Risk of Neurological Disorders: A Multicentre, Case-Control Study (COVIVAX)

Background: The attributable risk of common neurological disorders in participants exposed to COVID-19 vaccines is unknown and no case-control study has been performed. Methods: Observational, case-control study performed in 7 Italian centers. Consecutive individuals with a first diagnosis of a neurological disorder from January 2021 to December 2021 (cases), either vaccinated or unvaccinated, were recruited. Controls, either vaccinated or unvaccinated, were age- and sex-matched with cases. Primary outcome: the risk of developing new neurological disorders in vaccinated versus unvaccinated participants. Findings: 265 matched pairs were enrolled. At least one dose of any COVID-19 vaccine was received by 72.1% of cases and 79.6% of controls. The most frequent neurological diagnosis in cases were stroke (60.4%), multiple sclerosis (11.3%) and seizures (6.4%). In the univariable analysis, the risk of developing a new neurological disorder was reduced in vaccinated participants, compared to unvaccinated ones (OR 0.50; 95% CI 0.29-0.86; p=0.0114). In the multivariable analysis, after adjusting for comorbidities, education and exposure to COVID-19 or flu,  the number of doses received was directly associated with a reduced risk of developing new neurological disorders, as the number of doses increases, only for participants aged 60+ years (p=0.0472; OR 0.14, 95% CI 0.03-0.68, for 3+ doses), for those with pre-existing comorbidities (p=0.0122; OR 0.04, 95% CI 0.01-0.99, for 3+ doses) and for a diagnosis of stroke (p=0.0232; OR 0.14, 95% CI 0.02-0.97, for 3+ doses). Interpretation: The study provided no warning sign regarding the risk of developing new neurological disorders following COVID-19 vaccination of any type or doses. A potentially protective effect of multiple doses of COVID-19 vaccines against the risk of stroke in people aged 60+ and with pre-existing comorbidities needs to be confirmed and might affect public health policies at a global level. Funding: The study was supported by the Italian Society of Neurology. Declaration of Interest: E. Pupillo reports grants from the Italian Ministry of Health, grants from AIFA, outside the submitted work. A. Pilotto reports grans from IMI H2020 initiative, Ministry of Health (Minsal), Ministry of Education, Research and University (MIUR) and Airalzh, LIMPE-DISMOV foundation; speaker honoraria from Abbvie, Bial, Lundbeck, Lusofarmaco, Roche Pharma; travel support from Abbvie, Bial, Lundbeck, Lusofarmaco, Roche Pharma. P. Calabresi payment or honoraria for Abbvie, Bial, Bayer Schering, Biogen-Dompè, Biogen-Idec, Eisai, Lilly, Lundbeck, Lusofarmaco, Merck-Serono, Novartis, Sanofi-Genzyme, Teva, UCB Pharma, Zambon. A. Zini consulting fees for Boehringer-Ingelheim, CSL Behring and Angels Iniziative; payment or honoraria for Astra Zeneca and Daiichi-Sankio; payment for expert testimony for Alexion-Astra Zeneca. All other authors reports no disclosures. Ethical Approval: The study started on May 1st, 2021, after approval by the Ethics Commitee Ethics Committee Istituto Nazionale per le Malattie Infettive Lazzaro Spallanzani IRCCS Parere n. 27, Registro delle Sperimentazioni 2022, session of 24 February 2022