Neurological complications after first dose of COVID-19 vaccines and SARS-CoV-2 infection

The unprecedented speed and scale of COVID-19 vaccine development and deployment necessitate ongoing risk-benefit evaluations. While vaccines like ChAdOx1nCoV-19 and BNT162b2 have demonstrably reduced COVID-19 severity, clinical trials lacked the power to detect rare adverse neurological events. The identification of such events is a global priority. The increased risk of cerebral venous sinus thrombosis with ChAdOx1nCoV-19 led to restrictions on its use in some populations. Furthermore, case reports and surveillance studies have linked other neurological events, such as Guillain-Barré syndrome and myelitis, to both COVID-19 vaccination and infection, but these studies were limited by small sample sizes and potential biases. Therefore, a large-scale study investigating these associations was urgently needed.

Previous studies, including case reports and surveillance studies, suggested potential links between neurological adverse events and both COVID-19 vaccination and infection. However, these studies suffered from limitations such as small sample sizes, selection bias, and potential recording biases. The available data were insufficient to draw definitive conclusions about the magnitude and nature of these associations. The need for a large-scale, population-based study to overcome these limitations was highlighted.

This study used a self-controlled case series (SCCS) design. Data were obtained from the English National Immunisation Management System (NIMS) database linked to national data for mortality, hospital admissions, and SARS-CoV-2 infection. The study included over 32 million individuals who received their first dose of either ChAdOx1nCoV-19 or BNT162b2 vaccines between December 1, 2020, and May 31, 2021. Neurological outcomes were defined using ICD-10 codes from Hospital Episode Statistics (HES) and death certificates. The SCCS design controlled for fixed characteristics and adjusted for temporal confounding using weekly time blocks. Incidence rate ratios (IRRs) and 95% confidence intervals (CIs) were calculated to assess the association between vaccine doses or positive SARS-CoV-2 tests and neurological complications in pre-specified time periods (0, 1-7, 8-14, 15-21, and 22-28 days post-exposure). Sensitivity analyses were conducted to assess the robustness of the results. The study was replicated using an independent Scottish cohort. Subgroup analyses by age and sex were performed to investigate interactions. Finally, celiac disease and anaphylaxis were used as negative and positive control outcomes, respectively.

The study found an increased risk of Guillain-Barré syndrome (IRR 2.90, 95% CI 2.15–3.92 at 15–21 days post-vaccination) and Bell's palsy (IRR 1.29, 95% CI 1.08–1.56 at 15–21 days) with the ChAdOx1nCoV-19 vaccine. An increased risk of hemorrhagic stroke (IRR 1.38, 95% CI 1.12–1.71 at 15–21 days) was observed with the BNT162b2 vaccine. A Scottish cohort confirmed the association between ChAdOx1nCoV-19 and Guillain-Barré syndrome (IRR 2.32, 95% CI 1.08–5.02). Significantly higher risks of all neurological outcomes were observed after a positive SARS-CoV-2 test, with Guillain-Barré syndrome showing a particularly high IRR of 5.25 (95% CI 3.00–9.18). The study estimated 38 excess cases of Guillain-Barré syndrome per 10 million ChAdOx1nCoV-19 recipients and 145 excess cases per 10 million following a positive SARS-CoV-2 test. Subgroup analyses revealed a significant interaction between age and myasthenic disorder risk with ChAdOx1nCoV-19, and a higher hemorrhagic stroke risk with BNT162b2 in women. Sensitivity analyses generally supported the main findings. No increased risk of celiac disease was found (negative control), while anaphylaxis showed the expected increased risk (positive control).

This large population-based study provides crucial evidence on the rare neurological complications associated with COVID-19 vaccines and infection. The findings highlight a significantly greater risk of neurological complications following SARS-CoV-2 infection compared to vaccination. The association between ChAdOx1nCoV-19 and Guillain-Barré syndrome was robustly replicated in an independent cohort, lending strong support to this finding. The mechanistic reasons for the differential risks between the two vaccines remain unclear, warranting further research. The higher hemorrhagic stroke risk with BNT162b2 in women also needs further investigation. The study's strengths include its large sample size, population-based design, and the use of SCCS methodology to control for confounding. However, limitations include focusing on the first vaccine dose only, and the potential underestimation of milder cases not requiring hospitalization.

This study quantified the risk of several rare neurological adverse events associated with ChAdOx1nCoV-19 and BNT162b2 vaccines and SARS-CoV-2 infection. The significantly higher risk associated with infection compared to vaccination underscores the continued importance of vaccination programs. Clinicians should be aware of these rare but potentially disabling complications. Further research is needed to elucidate the mechanisms underlying these associations and to investigate the long-term consequences of these neurological events.

The study focused solely on the first vaccine dose, limiting the analysis of second-dose effects. The database's coding did not allow differentiation between Guillain-Barré syndrome variants. Milder cases not requiring hospitalization might be underrepresented. Some myasthenic disorder admissions could represent exacerbations of pre-existing conditions. The Scottish replication cohort's smaller size resulted in less precise estimates. The study was limited to data available until May 31, 2021, which means that some later-onset events may not be included.