Background: Several neurological manifestations shortly after a receipt of coronavirus infectious disease 2019 (COVID-19) vaccine have been described in the recent case reports. Among those, we sought to evaluate the risk of encephalitis and meningitis after COVID-19 vaccination in the entire South Korean population. Methods: We conducted self-controlled case series (SCCS) analysis using the COVID-19 immunization record data from the Korea Disease Control Agency between February 2021 and March 2022, linked with the National Health Insurance Database between January 2021 and October 2022. We retrieved all medical claims of adults aged 18 years or older who received at least one dose of COVID-19 vaccines (BNT162b2, mRNA-1273, ChAdOx1-S, or Ad26.COV2.S), and included only those who had a diagnosis record for encephalitis or meningitis within the 240-day post-vaccination period. With day 0 defined as the date of vaccination, risk window was defined as days 1–28 and the control window as the remainder period excluding the risk windows within the 240-day period. We used conditional Poisson regression to estimate the incidence rate ratios (IRR) with 95% confidence intervals (CI), stratified by dose and vaccine type. Results: From 129,956,027 COVID-19 vaccine doses administered to 44,564,345 individuals, there were 251 and 398 cases of encephalitis and meningitis during the risk window, corresponding to 1.9 and 3.1 cases per 1 million doses, respectively. Overall, there was an increased risk of encephalitis in the first 28 days of COVID-19 vaccination (IRR 1.26; 95% CI 1.08–1.47), which was only significant after a receipt of ChAdOx1-S (1.49; 1.03–2.15). For meningitis, no increased risk was observed after any dose of COVID-19 vaccine (IRR 1.03; 95% CI 0.91–1.16). Conclusions: Our findings suggest an overall increased risk of encephalitis after COVID-19 vaccination. However, the absolute risk was small and should not impede COVID-19 vaccine confidence. No significant association was found between the risk of meningitis and COVID-19 vaccination.
Keywords: COVID-19 vaccine; Encephalitis; Meningitis; Self-controlled case series
Supplementary Information The online version contains supplementary material available at https://doi.org/10.1186/s12916-024-03347-6.
Implementation of global mass vaccination campaign against coronavirus disease 2019 (COVID-19) has resulted in more than 5.5 billion people worldwide to receive a dose of COVID-19 vaccine [[
Encephalitis and meningitis are inflammation of the brain parenchyma and meninges, respectively, and are reported as one of the AESIs of COVID-19 [[
To address this research gap, we conducted a nationwide population-based study to evaluate the association between the two neurological events and COVID-19 vaccinations in the South Korea's healthcare database using a self-controlled case series (SCCS) analysis. COVID-19 vaccination in South Korea began in March 2021, with more than 86% of the population completing the primary series with one of the following COVID-19 vaccines: BNT162b2 (Pfizer-BioNTech), mRNA-1273 (Moderna), ChAdOx1-S (Oxford-AstraZeneca), Ad26.COV2.S (Janssen/Johnson & Johnson) [[
This study was a part of South Korea's COVID-19 Vaccine Safety Research Committee (CoVaSC) for establishing evidence to guide safe use of COVID-19 vaccines. CoVaSC utilizes a large-linked database by linking the COVID-19 immunization registry data from the Korea Disease Control and Prevention Agency and the National Health Insurance System Database (NHID). The linkage between the two data sources is deterministic, using the 13-digit Resident Registration Number issued to all residents of South Korea. Briefly, COVID-19 immunization registry data was delivered to the secure data storage server of NHID, where medical claims of COVID-19 vaccine recipients were extracted. Patient consents were not required for the data linkage as pertinent data were anonymized.
Briefly, COVID-19 immunization registry data contains comprehensive information on the demographics (i.e., sex, age at immunization, and nationality), COVID-19 vaccine administration (i.e., vaccine type, dose number, administration route, and vaccination site), and COVID-19 infection (i.e., date of positive test). NHID contains all medical claims of the entire South Korean population, including demographics, income-based insurance premium tier as a proxy for socioeconomic status, diagnoses, procedures, in-patient medication orders, out-patient prescriptions, and date of death through linkage to the national statistics data. Medical diagnoses are recorded using the International Classification of Diseases, 10th revision (ICD-10). More details on the two data sources are described elsewhere [[
From the large-linked database, we procured all claims data of 42 million individuals aged 18 years or older at their first COVID-19 vaccination between February 26, 2021, and October 31, 2022. Among them, we included those with a diagnosis record for encephalitis or meningitis after COVID-19 vaccination in the SCCS analysis.
Individuals who were vaccinated outside of South Korea, foreigners, or clinical trial enrollees were excluded as their healthcare utilization after COVID-19 vaccination may not be fully captured. Individuals with incomplete immunization record(s) such as missing vaccine type, dose number, etc. were also excluded to avoid any exposure misclassification. Individuals with a diagnosis record for encephalitis or meningitis in the 365 days prior to their first COVID-19 vaccine dose were excluded to capture only the incident outcomes. Lastly, those diagnosed with encephalitis or meningitis outside the hospital setting were excluded to improve the validity of the captured outcomes.
The outcomes of interest were encephalitis and meningitis after a receipt of COVID-19 vaccine. These neurological events were captured using ICD-10 codes and restricted to diagnoses made during hospitalization. To further improve the outcome validity, we required patients to have a procedural code for cerebrospinal fluid (CSF) test with the diagnosis record. This operational definition was adopted from previous literature and Brighton Collaboration case definitions for acute encephalitis and meningitis published by the Safety Platform for Emergency vACcines (SPEAC) [[
We used SCCS analysis to determine whether there is a transient increased risk of study outcome after COVID-19 vaccination. This analysis uses data from individuals who had experienced both exposure and outcome of interest in a pre-specified observation period. Comparison is made within the individual by comparing outcome incidence rates in a risk window on or after the date of exposure with a control window assumed to be unrelated to exposure. As the individuals are acting as their own control, this design inherently controls for time-fixed confounders such as demographics and pre-existing chronic medical conditions. Further details on SCCS design for vaccine safety research are described in depth elsewhere [[
The observation period was defined as a 240-day period from the date of the first COVID-19 vaccination. The risk window was defined as 1–28 days after each dose, and the control window as the remainder days within the observation period; the 28-day window was based on a systemic review of case reports that described an onset of encephalitis ranging from 1 to 30 days after COVID-19 vaccination [[
Descriptive analysis was conducted to summarize the characteristics of encephalitis and meningitis cases, stratified by outcome occurrence in the risk or control periods, using mean with standard deviation (SD) for continuous variables and frequencies with percentages for categorical variables. Demographics including age, sex, health insurance type, and residences were ascertained on the date of the first COVID-19 vaccination. Medical claims 365 days prior to the vaccination were analyzed to measure the Charlson comorbidity index (CCI) score and comorbidities including myocardial infarction, congestive heart failure, peripheral vascular disease, cerebrovascular disease, dementia, chronic pulmonary disease, rheumatic disease, peptic ulcer disease, hepatic disease, diabetes mellitus, renal disease, cancer and Human immunodeficiency virus infection.
For the SCCS analysis, the number of events and time under exposure were measured to estimate the incidence rate per person-year in the risk and control windows. The conditional Poisson regression model was used to estimate the incidence rate ratios (IRR) and 95% confidence intervals (CI), comparing the rate in the risk window with the control window, for each outcome of interest. The IRRs were presented overall, and stratified by scheduled dose (i.e., first, second, and third doses) and vaccine type, and post-hoc subgroup analyses were conducted according to age group (10-year bands), sex, and comorbidities.
We conducted sensitivity analyses to test the robustness of findings against various assumptions made in this study. First, to test the impact of different risk window lengths on the study outcomes, we repeated the analyses using the shorter and longer risk windows of 14 days and 42 days, respectively. Second, to test the robustness of case definitions for capturing the study outcomes, analyses were conducted by: (
The analyses were conducted separately for encephalitis and meningitis by constructing two separate case groups for SCCS analysis. All analyses were conducted using SAS version 9.4 (SAS Institute Inc., Cary, NC, USA), and a 2-sided α of less than 0.05 was considered statistically significant.
From 129,956,027 COVID-19 vaccine doses administered to 44,564,345 individuals, there were 796 encephalitis and 1,362 meningitis cases included in the SCCS analysis (Fig. 1).
Graph: Fig. 1Study flow chart. Abbreviations: COVID-19, coronavirus infectious disease 2019; SCCS, self-controlled case series
Of the encephalitis cases, there were 251 cases identified in the risk window, corresponding to 1.9 cases per 1 million doses. Their mean age (SD) at first COVID-19 vaccination was 56.9 years (18.0) and 57.8% were men (Table 1).
Table 1 Baseline characteristics of encephalitis and meningitis cases after COVID-19 vaccination, stratified by exposure windows
Characteristic Encephalitis Meningitis 56.9 (18.0) 56.3 (18.8) 0.722 45.1 (18.8) 44.7 (18.7) 0.671 18–29 33 (13.1) 72 (13.2) 0.342 109 (27.4) 270 (28) 0.747 30–39 12 (4.8) 40 (7.3) 75 (18.8) 181 (18.8) 40–49 30 (12.0) 71 (13) 57 (14.3) 139 (14.4) 50–59 46 (18.3) 92 (16.9) 45 (11.3) 128 (13.3) 60–69 67 (26.7) 109 (20) 64 (16.1) 122 (12.7) 70–79 43 (17.1) 110 (20.2) 34 (8.5) 87 (9) 80 + 20 (8.0) 51 (9.4) 14 (3.5) 37 (3.8) 0.270 0.518 Male 145 (57.8) 292 (53.6) 200 (50.3) 503 (52.2) Female 106 (42.2) 253 (46.4) 198 (49.7) 461 (47.8) 0.782 0.080 NHI 235 (93.6) 513 (94.1) 381 (95.7) 940 (97.5) Medical aid 16 (6.4) 32 (5.9) 17 (4.3) 24 (2.5) 0.314 0.268 Metropolitan 182 (72.5) 376 (69) 287 (72.1) 666 (69.1) Rural 69 (27.5) 169 (31) 111 (27.9) 298 (30.9) CCI (mean, SD) 2.0 (2.6) 1.9 (2.3) 0.771 1.3 (2.2) 1.2 (2) 0.345 CCI < 5 219 (87.3) 479 (87.9) 0.799 357 (89.7) 899 (93.3) 0.026 CCI ≥ 5 32 (12.7) 66 (12.1) 41 (10.3) 65 (6.7) Myocardial infarction 5 (2.0) 4 (0.7) 0.119 4 (1) 7 (0.7) 0.601 Congestive heart failure 17 (6.8) 36 (6.6) 0.930 20 (5) 22 (2.3) 0.008 Peripheral vascular disease 36 (14.3) 83 (15.2) 0.744 31 (7.8) 79 (8.2) 0.803 Cerebrovascular disease 36 (14.3) 64 (11.7) 0.304 26 (6.5) 58 (6) 0.719 Dementia 22 (8.8) 51 (9.4) 0.788 19 (4.8) 41 (4.3) 0.670 Chronic pulmonary disease 50 (19.9) 112 (20.6) 0.837 64 (16.1) 150 (15.6) 0.810 Rheumatic disease 9 (3.6) 32 (5.9) 0.175 18 (4.5) 26 (2.7) 0.083 Peptic ulcer disease 40 (15.9) 101 (18.5) 0.373 70 (17.6) 138 (14.3) 0.127 Hepatic disease 63 (25.1) 129 (23.7) 0.661 73 (18.3) 188 (19.5) 0.621 Diabetes mellitus 57 (22.7) 141 (25.9) 0.338 59 (14.8) 146 (15.1) 0.880 Renal disease 8 (3.2) 30 (5.5) 0.154 9 (2.3) 27 (2.8) 0.572 Cancer 25 (10.0) 35 (6.4) 0.079 26 (6.5) 43 (4.5) 0.113 HIV infection 1 (0.4) 0 (-) 0.140 1 (0.3) 3 (0.3) 0.853
Abbreviations: COVID-19 Coronavirus infectious disease 2019, SD Standard deviation, NHI National Health Insurance, CCI Charlson comorbidity index, HIV Human immunodeficiency virus
Overall, there was an increased risk of encephalitis in the first 28 days after any doses of COVID-19 vaccine (IRR 1.26; 95% CI 1.08–1.47). When stratified by scheduled dose, there was a trend towards increased risk for first dose (IRR 1.19; 95% CI 0.97–1.47), whereas no risk for the second (0.96; 0.76–1.20) and third doses (0.92; 0.67–1.26). In the stratified analysis by vaccine type, significant risk was present only after a receipt of ChAdOx1-S (IRR 1.49; 95% CI 1.03–2.15) (Table 2).
Table 2 Risk of encephalitis after COVID-19 vaccination, overall and stratified by scheduled dose and vaccine type
251 545 134.8 369.3 1.86 1.48 1.26 (1.08–1.47) 1st dose 106 545 60.2 369.3 1.76 1.48 1.19 (0.97–1.47) 2nd dose 87 438 53.2 256.5 1.63 1.71 0.96 (0.76–1.20) 3rd dose 58 83 21.3 28.2 2.72 2.94 0.92 (0.67–1.26) BNT162b2 123 279 69.2 188.0 1.78 1.48 1.20 (0.96–1.49) mRNA-1273 21 62 13.6 36.5 1.54 1.70 0.91 (0.54–1.52) ChAdOx1-S 44 110 19.7 73.1 2.23 1.50 1.49 (1.03–2.15) Ad26.COV2.S 0 7 0.5 3.4 - 2.07 -
Abbreviations: COVID-19 Coronavirus infectious disease 2019, IRR Incidence rate ratio, CI Confidence interval
While the risks were generally non-significant in the majority of subgroups owing to few cases in each stratum, the point estimates were largely consistent with the main findings. Notably, the risk was significant among those aged between 60 and 69 years (IRR 1.64; 95% CI 1.21–2.24), with underlying cerebrovascular disease (1.57; 1.05–2.37), and cancer (1.94; 1.16–3.25) (Additional file 1: Table S2). The results of sensitivity analyses remained largely consistent with the main findings; the risk remained significant using the shorter and longer risk windows of 14 days (IRR 1.22; 95% CI 1.01–1.46) and 42 days (1.30; 1.13–1.50), respectively (Additional file 1: Table S3–S5).
For meningitis, there were 398 cases in the risk window, corresponding to 3.1 cases per 1 million doses. Meningitis cases were relatively young, with a mean age (SD) of 45.1 years and 50.3% were men (Table 1).
There was no increased risk of meningitis in the first 28 days after any doses of COVID-19 vaccine (IRR 1.03; 95% CI 0.91–1.16), and the findings remained consistent when stratified by scheduled dose (1.10; 0.94–1.29 for first dose; 0.91; 0.76–1.09 for second dose; and 0.76; 0.57–1.00 for third dose). In the stratified analysis by vaccine type, the risk tended to associate with non-mRNA-based vaccines, with significant risk noted after a receipt of Ad26.COV2.S (IRR 4.22; 95% CI 1.22–14.59) and a trend towards increased risk for ChAdOx1-S (1.45; 0.99–2.11) (Table 3).
Table 3 Risk of meningitis after COVID-19 vaccination, overall and stratified by scheduled dose and vaccine type
398 964 252.8 628.9 1.57 1.53 1.03 (0.91–1.16) 1st dose 178 964 105.4 628.9 1.69 1.53 1.10 (0.94–1.29) 2nd dose 147 784 98.3 478.1 1.50 1.64 0.91 (0.76–1.09) 3rd dose 73 134 49.2 68.6 1.49 1.95 0.76 (0.57–1.00) BNT162b2 213 509 137.1 326.9 1.55 1.56 1.00 (0.85–1.17) mRNA-1273 59 156 41.9 104.4 1.41 1.49 0.94 (0.69–1.29) ChAdOx1-S 41 106 19.3 72.3 2.12 1.47 1.45 (0.99–2.11) Ad26.COV2.S 4 7 0.8 6.2 4.74 1.12 4.22 (1.22–14.59)
Abbreviations: COVID-19 Coronavirus infectious disease 2019, IRR Incidence rate ratio, CI Confidence interval
In the subgroup analysis, an increased risk of meningitis was observed among those with CCI score of 5 or higher (IRR 1.54; 95% CI 1.04–2.29) or congestive heart failure (2.18; 1.20–3.95), whereas null association was found across all other selected subgroups (Additional file 1: Table S6). The results of sensitivity analyses remained largely consistent with the main findings (Additional file 1: Table S7–S9).
In this nationwide population-based study using a large-linked database between the national COVID-19 immunization registry and administrative claims data, we found a positive association for encephalitis in the COVID-19-vaccinated adults between 2021 and 2022. We observed a transient risk of post-vaccination encephalitis, which was mainly driven by the events recorded in the 28 days after the first dose and ChAdOx1-S. While no significant risk of meningitis was found in the combined analysis of all COVID-19 vaccine doses, there was a heterogeneity in the risk across the vaccine type, with the significant risk observed after a receipt of Ad26.COV2.S.
Our findings on the risk of encephalitis after COVID-19 vaccination complement the previously reported trends toward increased risk in the population-based studies. In a study of 4.3 million adults vaccinated with ChAdOx1-S recorded in the UK primary care records data between December 2020 and May 2021, standardized IRR of post-vaccination encephalomyelitis, compared with pre-pandemic era (2017–2019), was 1.45 (95% CI 0.80–2.62) [[
Our finding on the null association between meningitis and COVID-19 vaccination was certainly unexpected, especially given that encephalitis and meningitis share similarities in clinical presentation and etiology [[
There was a heterogeneity in the risk of encephalitis and meningitis according to the type of COVID-19 vaccines. Existing data have indicated better safety profiles for the mRNA-based vs. non-mRNA-based vaccines [[
Emerging data suggests that encephalitis and meningitis after COVID-19 vaccination are non-infectious immune-mediated conditions, with proposed mechanisms including direct triggering of inflammatory cytokines by the vaccine and molecular mimicry between SARS-CoV-2 spike protein and myelin basic protein [[
In the subgroup analyses, we observed patients with pre-existing comorbidities including cerebrovascular disease, congestive heart failure, and malignancy were at increased risk of post-vaccination encephalitis or meningitis. Assuming that all identified cases were triggered by systemic inflammatory response against COVID-19 vaccine, these comorbidities might have predisposed patients at a greater risk of post-vaccination encephalitis or meningitis. For instance, blood–brain barrier disruption from prolonged brain ischemia can lead patients with cerebrovascular diseases susceptible to neuroinflammation [[
In this study, we presented real-world evidence on the safety of COVID-19 vaccinations through an assessment of the risk of the post-vaccination encephalitis or meningitis using the large-linked database representative of entire South Korean adults who received at least one dose of COVID-19 vaccines. The large sample size enabled us to estimate precise risk estimates for each outcome according to vaccine type, which could not be assessed in the clinical trials or observational studies with limited statistical power. The use of SCCS analysis allowed us to avoid bias arising from comparing COVID-19 vaccinated vs. unvaccinated individuals, and the within individual comparison removed any potential for confounding by time-invariant confounders.
There are several limitations to be considered when interpretating our study's findings. First, there is a potential for misclassification or inaccuracy of the captured outcomes as we relied on the ICD-10 codes for case definition, and this may either over- or under-estimate the true incidences of post-vaccination encephalitis and meningitis. To address this, we have adopted definitions from the previous literature and case definition published by the Brighton Collaboration, thereby restricting our cases to those diagnosed in hospital settings and received CSF tests. Nonetheless, it should be noted that the exact etiology or subtypes of encephalitis and meningitis could not be ascertained due to the lack of imaging or CSF results in the database. Specifically, we could not differentiate between autoimmune and infectious encephalitis or meningitis, and thus, it is certainly possible that pathogens, not COVID-19 vaccine, may be responsible for some of the cases identified after COVID-19 vaccination. Second, there may be a delay between the actual disease onset and diagnosis recorded in the database, and this may have impacted our study findings if the onset and diagnosis did not occur in the risk window. However, the results from sensitivity analysis by varying the length of risk windows were comparable to that of the main analysis. Third, the impact of concurrent COVID-19 infection on our findings cannot be fully ruled out. COVID-19 itself has been shown to be associated with neurological complications [[
This large population-based study assessed the risk of two rare neurological complications after COVID-19 vaccination. Our findings underscore a transient risk of post-vaccination encephalitis and meningitis, which were likely to be attributed to the first scheduled dose and non-mNRA platform COVID-19 vaccines. However, it is important to note that the absolute risk was small and should not impede COVID-19 vaccine confidence. Rather, the finding is to inform clinical practice to enable prompt diagnosis and treatment for patients presenting with neurological signs after COVID-19 vaccination. Moreover, further studies are needed to confirm the differential magnitude of the risk estimates for encephalitis and meningitis observed in this study as these two neurological events share similar etiology.
The authors thank the Korea Disease Control and Prevention Agency, the National Academy of Medicine of Korea, and the National Health Insurance Service (NHIS) for their collaborative effort in making the nationwide data readily available for analysis and providing necessary assistance to conduct this study.
JHK, DY, HYK, KJ, and JYS designed the research. JHK analyzed the data. JHK, DY, HYK, KJ, JSS, WCS, JIB, and JYS interpreted the results. JHK drafted the manuscript. DY, HYK, KJ, JIB, and JYS supervised the manuscript. All authors read and approved the final manuscript.
This study was supported by a grant (Grant No. 2021–05-008) of the Korea Disease Control and Prevention Agency. The funders of the study had no role in study design, data collection, data analysis, data interpretation, or writing of the manuscript. The corresponding authors had full access to all the data in the study and had final responsibility for the decision to submit for publication.
The data from this study are available from the Korea Disease Control and Prevention Agency and National Health Insurance Service. While legal data-sharing agreements prohibit data from being made publicly available, access may be granted upon reasonable request with specific data needs, analysis plans, and dissemination plans submitted to the Korea Disease Control and Prevention Agency and National Health Insurance Service.
This study was approved by the Public Institutional Review Board Designated by the Ministry of Health and Welfare (P01-202203–01-005) and performed in accordance with the principles of the Declaration of Helsinki. The need for informed consent was waived as this study was performed using anonymized claims data.
Not applicable.
Dr. Shin received grants from the Ministry of Food and Drug Safety, the Ministry of Health and Welfare, the National Research Foundation of Korea, and the Government-wide R&D Fund for Infectious Disease Research and Pharmaceutical Companies, including Pfizer, UCB, and LG Chem. No other relationships or activities have influenced the submitted work.
Graph: Additional file 1: Table S1. Diagnostic and procedure codes for encephalitis and meningitis in the national health insurance system database. Table S2. Subgroup analysis on the risk of encephalitis after COVID-19 vaccination according to the selected characteristics. Table S3. Sensitivity analysis on the risk of encephalitis after COVID-19 vaccination by varying the risk window lengths. Table S4. Sensitivity analysis on the risk of encephalitis after COVID-19 vaccination by varying the case definition.Table S5. Sensitivity analysis on the risk of encephalitis after COVID-19 vaccination in the modified study population. Table S6. Subgroup analysis on the risk of meningitis after COVID-19 vaccination according to the selected characteristics. Table S7.Sensitivity analysis on the risk of meningitis after COVID-19 vaccination by varying the risk window lengths. Table S8. Sensitivity analysis on the risk of meningitis after COVID-19 vaccination by varying the case definition. Table S9. Sensitivity analysis on the risk of meningitis after COVID-19 vaccination in the modified study population.
• AESI
- Adverse event of special interest
• CCI
- Charlson comorbidity index
• CI
- Confidence interval
• CoVaSC
- COVID-19 Vaccine Safety Research Committee (CoVaSC)
- COVID-19
- Coronavirus infectious disease 2019
• CSF
- Cerebrospinal fluid
• GBS
- Guillain-Barré syndrome
• ICD-10
- International Classification of Diseases, 10th revision
• IgG
- Immunoglobulin G
• IRR
- Incidence rate ratio
• NHID
- National Health Insurance System Database
- SARS-CoV-2
- Severe acute respiratory syndrome coronavirus 2
• SCCS
- Self-controlled case series
• SD
- Standard deviation
• SPEAC
- Safety Platform for Emergency vACcines
• UK
- United Kingdom
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By Ju Hwan Kim; Dongwon Yoon; Hwa Yeon Ko; Kyungyeon Jung; Jun-Sang Sunwoo; Won Chul Shin; Jung-Ick Byun and Ju-Young Shin
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