The COVIVAX study investigated the attributable risk of common neurological disorders in previously neurologically-healthy persons exposed to COVID-19 vaccines, using a case-control study design. The frequency of newly diagnosed neurological disorders (approximately 60% stroke, 11% multiple sclerosis, 6% epilepsy) and vaccinated versus unvaccinated participants (approximately 75% versus 25%) reflected the predominantly hospital-based recruitment and the timing of the study conduction with regards to the COVID-19 vaccination campaign.
Our findings clearly indicate that exposure to COVID-19 vaccines, regardless of type or number of doses, does not increase the risk of newly diagnosed common neurological disorders, in particular stroke, multiple sclerosis and epilepsy. Conversely, our results suggested a potentially protective effect of COVID-19 vaccination against stroke in persons aged over 60 and with comorbidities who received multiple doses of vaccine. Although methodologically robust, we believe that this latter finding should be interpreted with caution and further studies are needed to confirm this observation, considering the limited sample size of the present study.
No difference in disease-related disability at hospital discharge was observed between vaccinated and unvaccinated participant, indicating no sign of increased disease severity associated with COVID-19 vaccination. Moreover, over 90% of cases were follow-up for 12 months and the course of neurological disorders was not different than expected in either vaccinated or unvaccinated participants.
Traditional case-controlled studies have the advantages of being more accurate for cumulative exposures (e.g. multiple dose of vaccine) and disorders with increased mortality (e.g. stroke), compared to self-controlled studies20. The results of two previous, large studies specifically focused on neurological safety of COVID-19 vaccines are available, both of them used a self-controlled study design, routinely collected or administrative data as data sources and were mostly focused on immune-mediated neurological disorders. A first, self-controlled study including over 30 million people who received only the first dose of ChAdOx1nCoV-19 or BNT162b2 estimated a slightly increased risk of Guillain-Barré syndrome (38 excess cases per 10 million people) after receiving the ChAdOx1nCoV-19 vaccine and a possibly increases risk of hemorrhagic stroke (60 excess cases per 10 million people; however, this magnitude was reduced in sensitivity analyses that accounted for fatal events) after received the BNT162b2 vaccine21. A second, self-controlled study including over 8 million people who received at least one dose of COVID-19 vaccines (ChAdOx1 nCoV-19, BNT162b2, mRNA-1273, or Ad.26.COV2.S) showed no higher than expected rates of immune-mediated neurological disorders, in particular Bell's palsy, encephalomyelitis, and Guillain-Barré syndrome22.
Our study has strengths and limitations. Cases were exclusively recruited by neurologists who were involved in patient’s management. This neurologist-centered approach of patient ascertainment had the major advantage of high standards of diagnostic accuracy and disease management, which was guaranteed by specialized medical professionals, with direct consequences on disease definitions and data collection, compared to administrative data. Moreover, the cases recruited in the COVIVAX study reflected the epidemiology of newly diagnosed common neurological disorders, such as stroke, multiple sclerosis and epilepsy. Data from age- and sex-matched controls have not been collected by previous studies, thus the COVIVAX study added methodological strength and novelty to the previous evidence available on this topic.
A major limitation was the limited sample size, which allowed us to estimate the attributable risk only for common neurological disorders, such as stroke, multiple sclerosis or epilepsy. Other rarer neurological conditions were under-represented in our study, in particular immune-mediated disorders such as Guillain-Barrè syndrome or encephalitis, and our results were not powered to make any inference about them. However, this study was performed during the pandemic (year 2021), while the Italian health system was still considerably under pressure. This led the Investigators to collect a limited number of cases and matched controls.
The COVIVAX study provided no warning sign regarding the risk of developing new neurological disorders, in particular stroke and multiple sclerosis, 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 over 60 and with comorbidities was unexpected, needs to be confirmed by further studies and might affect public health policies at a global level.