ABSTRACT
Purpose
To assess adverse neurological risks following influenza vaccination in older adults.
Methods
Using a linked database of healthcare administrative claims data and vaccination records from an urban city in Japan (April 1, 2014, to March 31, 2020), we conducted an observational study utilizing a self‐controlled case series design. We identified individuals aged ≥ 65 years who experienced adverse neurological outcomes, defined as hospitalizations related to epilepsy, paralysis, facial paralysis, neuralgia, neuritis, optic neuritis, migraine, extrapyramidal disorders, Guillain–Barre syndrome, or narcolepsy. We used conditional Poisson regression to analyze within‐subject incidence rate ratios, comparing the risk of these outcomes during risk periods following influenza vaccination (0–6 days and 7–29 days after each vaccination) with nonvaccination periods. Our analysis was adjusted for age and season groups as time‐varying covariates.
Results
We enrolled 3283 eligible individuals (men: 1643; mean [standard deviation] age: 76 [7.3] years). The incidence rate ratio for the outcome during the risk periods was 0.93 (95% confidence interval, 0.66–1.30) in risk period 1 (0–6 days after vaccination) and 1.14 (0.96–1.35) in risk period 2 (7–29 days after vaccination), respectively.
Conclusions
We found no evidence that the risk of adverse neurological events was increased after influenza vaccination in older adults. These results may help reassure older adults who are hesitant to receive influenza vaccination because of concerns regarding adverse neurological outcomes.
Keywords: neurology, observational study, pharmacoepidemiology, self‐controlled study design, vaccine safety
Summary.
Neurological event risk post‐influenza vaccination has been poorly assessed in older adults.
This study used healthcare claim data and vaccination records to assess risk.
The risks for neurological outcomes were evaluated using the self‐controlled case series design.
The apparent risk increase was not confirmed in older adults in Japan.
Findings suggested that vaccination was safe against adverse neurological events.
Abbreviations
- CI
confidence interval
- COVID‐19
coronavirus disease 2019
- ICD‐10
International Classification of Diseases 10th revision
- IRR
incidence rate ratio
- SCCS
self‐controlled case series
- SD
standard deviation
1. Introduction
Influenza is a highly contagious acute viral infection associated with significant morbidity and mortality. Vaccination is crucial for preventing infection and reducing serious complications, particularly in older adults (age ≥ 65 years) who exhibit high mortality rates from influenza [1, 2, 3, 4]. In Japan, routine influenza vaccination is recommended for individuals aged ≥ 65 years and those aged 60–64 years with underlying medical conditions, such as impaired heart, kidney, or respiratory functions [5]. Several developed countries have recommended influenza vaccination for older adults for decades, with an increasing trend in developing countries [6].
Several case reports have linked influenza vaccination with potential neurological adverse events such as polyneuropathy [7] and optic neuritis [8, 9, 10]. One cohort study identified a higher risk of Bell's palsy among vaccinated individuals than among those who were unvaccinated. Individuals aged 60 years and older comprised 21.2% of the cohort [11]. A self‐controlled study identified an increased risk of hospitalization for Guillain–Barre syndrome after vaccination [12]. On the other hand, some previous studies showed no increase in the risk of neurological adverse events such as epilepsy [13, 14], facial palsy [15, 16, 17], and Guillain–Barre syndrome [11, 18, 19] after vaccination. Notably, only two of these studies specifically targeted older adults [15, 17], leaving the association between vaccination and adverse neurological effects in older adults uncertain. Given the extensive use of influenza vaccination, the risk of adverse events must be evaluated in older adults using comprehensive real‐world datasets.
In this study, we investigated the risk of adverse neurological effects after influenza vaccination. Using linked health insurance claim data and vaccination records from an urban city in Japan, we conducted a retrospective study utilizing the self‐controlled case series (SCCS) design [20, 21].
2. Methods
2.1. Data Source
We used administrative claim data linked to influenza vaccination records maintained by the municipality of an urban city in Japan (City A). The study period spanned from April 2014 to March 2020. We did not use data after April 2020, considering the influence of the COVID‐19 pandemic in Japan.
The administrative claim data comprised claims from the National Health Insurance, which is for self‐employed or retired individuals and their dependents, and claims from the advanced elderly medical service system, for individuals aged ≥ 75 years. These records include information on outpatient clinic visits, hospital admissions, and enrollees' age, sex, and diagnoses coded according to the International Classification of Diseases, 10th revision (ICD‐10). The vaccination records included information on vaccine types and vaccination dates. Administrative claim data were linked to vaccination records using unique identification numbers. Deidentified data were provided to the researchers after linking the claims and vaccination records using personal identification.
This study was approved by the Research Ethics Committee, Graduate School of Medicine and Faculty of Medicine, the University of Tokyo (approval no. 2021187NI‐(3)). As our analyses involved the secondary use of anonymized data routinely collected by the Japanese government, the need for individual informed consent was waived following the current ethical guidelines for medical and health research involving human participants in Japan.
2.2. Study Design
We applied the SCCS design, which utilizes data solely from individuals experiencing the event of interest and automatically controls for the effect of time‐invariant confounders without explicit adjustments. This design is particularly suitable for studying the safety of vaccines and medicines using electronic medical databases that may typically lack comprehensive covariate information [21].
2.3. Study Population
We identified older adults (aged ≥ 65 years) who developed outcomes (defined later) using claim data from at least one of the National Health Insurance and Advanced Elderly Medical Service Systems. Their observation periods started at the latest of insurance eligibility, the data use initiation, and the 65th birthday and ended at the earlier of the study period's end (i.e., March 31, 2020) and the last day of insurance eligibility.
2.4. Exposure and Risk Periods
We defined exposure as influenza vaccination, establishing two risk periods and a pre‐exposure period for each vaccination [13]. Risk period 1 spanned 0–6 days after each vaccination (day 0 being the vaccination day), while risk period 2 spanned 7–29 days after each vaccination. Pre‐exposure periods were defined as 1–30 days before each vaccination. These pre‐exposure periods were analyzed separately owing to potential influences of neurological events on vaccination probability [22]. As influenza vaccination is typically administered once a year, overlaps between pre‐exposure and exposure periods were not considered. We did not find any overlap among individuals who experienced outcomes during the observation periods. The control period encompassed the remainder of the observation period, excluding the risk and pre‐exposure periods. Individuals were eligible to receive multiple vaccinations throughout the observation period. Figure 1 contains a graphical representation of the study timeline.
FIGURE 1.
Graphical representation of the study timeline.
2.5. Outcomes
The primary outcome was hospitalization associated with the diagnosis records of any of the following neurological diseases defined by ICD‐10 codes: epilepsy (ICD‐10 code: G40‐, G41‐), paralysis (G822, G825, G833), facial paralysis (G510), neuralgia and neuritis (M792), optic neuritis (H46‐, H477), migraine (G43‐), extrapyramidal disorders (G25‐), Guillain–Barre syndrome (G610), or narcolepsy (G474). Secondary outcomes included hospitalizations specifically for epilepsy and those for the aforementioned neurological diseases excluding epilepsy, separately. Each disease was confirmed using ICD‐10 codes, excluding those flagged as suspected diseases. Outcomes with an interval of < 30 days were regarded as a series of episodes, and only those with the first episode (at the initial onset date) were considered as outcomes.
2.6. Statistical Analyses
We described the participants' characteristics, including the duration of each period. To check one of the SCCS assumptions that the outcome occurrence does not influence subsequent exposure [22], for participants vaccinated in one vaccination season, we also tabulated whether they experienced an outcome during the corresponding risk period and whether they were vaccinated in the next vaccination season.
The within‐person incidence rate ratios (IRRs) of influenza vaccination for the three outcomes (i.e., primary outcome and two secondary outcomes) were estimated using conditional Poisson regression models. We conducted the analyses with adjustment for time‐varying covariates, including age groups (65–69, 70–74, 75–79, 80–84, 85–89, and ≥ 90 years) and season groups (March–May, June–August, September–November, and December–February). Additionally, we conducted a subgroup analysis of the groups stratified by sex.
Three sensitivity analyses were performed to assess the variability of arbitrariness in our analysis settings. First, we redefined risk period 2 as 7–41 days after each vaccination. Second, we redefined the pre‐exposure period as 1–42 days before each vaccination. Third, we changed the setting of the season groups in two ways: (February–April, May–July, August–October, and November–January) and (January–March, April–June, July–September, and October–December). All statistical analyses were conducted using R Statistical Software (version 4.2.1; R Core Team) with the “SCCS” (version 1.6) R package.
3. Results
Figure 2 illustrates the participant selection process flow diagram for the composite neurological outcomes. Of 545 072 enrollees with claims data in City A, 3283 older adult participants experienced the primary outcome (i.e., composite neurological outcomes based on all neurological diseases) during their observation periods. Figures S1 and S2 depict flow diagrams for outcomes related to epilepsy and neurological diseases other than epilepsy, respectively.
FIGURE 2.
Flow diagram of participant selection for outcomes based on all neurological diseases.
Table 1 presents the characteristics of the study population according to each outcome definition. The proportions of men and women were nearly equal for all outcome definitions, with a mean age of approximately 76 years at the beginning of the observation period for all outcome definitions. Vaccination records were concentrated from October to January, and each individual received an average of approximately 0.5 doses per vaccination season. Table 2 depicts vaccination patterns in the subsequent vaccination season among individuals vaccinated during the current season. For each outcome definition, the proportions of vaccinated individuals in the next season did not show substantial differences between those with and without outcome events during the risk periods of the current season. This finding supports our SCCS assumption that the occurrence of outcomes does not appear to influence subsequent vaccination behavior.
TABLE 1.
Characteristics of the participants in the analysis population for each outcome.
| Outcome type | |||
|---|---|---|---|
| Neurological | Epilepsy only | Other than epilepsy | |
| Participant, n | 3283 | 2690 | 673 |
| Sex, n (%) | |||
| Men | 1643 (50) | 1367 (51) | 317 (47) |
| Women | 1640 (50) | 1323 (49) | 356 (53) |
| Age at index date, Mean (SD), years | 76 (7.3) | 76 (7.3) | 76 (7.2) |
| No. of vaccinations per vaccination season | 0.52 | 0.52 | 0.51 |
| Length, mean (SD), days | |||
| Observation | 1628 (666) | 1591 (676) | 1786 (593) |
| Risk | 68 (64) | 67 (63) | 74 (68) |
| Control | 1492 (618) | 1457 (626) | 1638 (556) |
| Pre‐exposure | 68 (64) | 67 (63) | 74 (68) |
| Total length, n (%), person‐years | |||
| Observation | 14 630 (100) | 11 719 (100) | 3291 (100) |
| Risk | 611 (4) | 492 (4) | 136 (4) |
| Control | 13 408 (92) | 10 733 (92) | 3019 (92) |
| Pre‐exposure | 611 (4) | 493 (4) | 136 (4) |
| Age category, n (%), person‐years | |||
| 65–69 | 1868 (13) | 1516 (13) | 419 (13) |
| 70–74 | 2784 (19) | 2197 (19) | 662 (20) |
| 75–79 | 3618 (25) | 2852 (24) | 836 (25) |
| 80–84 | 3358 (23) | 2710 (23) | 747 (23) |
| 85–89 | 2019 (14) | 1652 (14) | 421 (13) |
| ≥ 90 | 983 (7) | 793 (7) | 206 (6) |
| Season category, n (%), person‐years | |||
| March–May | 3709 (25) | 2972 (25) | 833 (25) |
| June–August | 3746 (26) | 3006 (26) | 837 (25) |
| September–November | 3639 (25) | 2915 (25) | 819 (25) |
| December–February | 3536 (24) | 2826 (24) | 802 (24) |
Abbreviation: SD, standard deviation.
TABLE 2.
Vaccination behavior in the next vaccination season between individuals with and without outcome experience in the risk periods of the current vaccination season.
| Vaccination in the next vaccination season | ||||
|---|---|---|---|---|
| Outcome type | Experienced outcome in risk period of current vaccination season | Yes | No | Proportion of vaccinated individuals |
| Neurological | Yes | 92 | 14 | 0.87 |
| No | 4508 | 819 | 0.85 | |
| Epilepsy | Yes | 83 | 13 | 0.86 |
| No | 3578 | 662 | 0.84 | |
| Other than epilepsy | Yes | 10 | 1 | 0.91 |
| No | 1069 | 178 | 0.86 | |
Table 3 presents the main results of the conditional Poisson regression with adjustments for age and season. We did not observe an increase in risk for each outcome during the risk periods compared to the control periods. The IRRs for the primary outcome (i.e., composite outcome based on all neurological diseases) during the risk periods were 0.93 (95% confidence interval (CI): 0.66–1.30) in risk period 1 and 1.14 (95% CI: 0.96–1.35) in risk period 2. For the outcome based on epilepsy, the IRRs were 1.07 (95% CI: 0.76–1.51) in risk period 1 and 1.14 (95% CI: 0.94–1.37) in risk period 2. For the outcome based on neurological diseases other than epilepsy, the IRRs were 0.41 (95% CI: 0.13–1.29) in risk period 1 and 0.97 (95% CI: 0.63–1.49) in risk period 2. Although the point estimate of the IRR for the outcome based on neurological diseases other than epilepsy was < 1 in risk period 1, the corresponding 95% CI was wide.
TABLE 3.
Within‐person incidence rate ratios estimated using conditional Poisson regression adjusted for age and seasonal categories for each outcome in the self‐controlled case series analyses.
| Outcome type | ||||||
|---|---|---|---|---|---|---|
| Neurological | Epilepsy | Other than epilepsy | ||||
| Period | ||||||
| No. of events | IRR (95% CI) | No. of events | IRR (95% CI) | No. of events | IRR (95% CI) | |
| Control | 5092 | 1 (ref) | 4374 | 1 (ref) | 785 | 1 (ref) |
| Pre‐exposure | 63 | 0.96 (0.81–1.13) | 55 | 0.98 (0.81–1.18) | 9 | 0.77 (0.50–1.18) |
| Risk 1 | 47 | 0.93 (0.66–1.30) | 44 | 1.07 (0.76–1.51) | 4 | 0.41 (0.13–1.29) |
| Risk 2 | 177 | 1.14 (0.96–1.35) | 154 | 1.14 (0.94–1.37) | 24 | 0.97 (0.63–1.49) |
| Age | ||||||
| 65–69 | 693 | 1 (ref) | 590 | 1 (ref) | 113 | 1 (ref) |
| 70–74 | 940 | 1.83 (1.54–2.18) | 798 | 1.98 (1.64–2.39) | 157 | 1.29 (0.85–1.95) |
| 75–79 | 1231 | 3.84 (3.05–4.83) | 1036 | 4.38 (3.40–5.64) | 209 | 2.01 (1.18–3.43) |
| 80–84 | 1229 | 9.64 (7.35–12.64) | 1069 | 12.56 (9.32–16.91) | 170 | 2.39 (1.26–4.54) |
| 85–89 | 829 | 23.41 (17.11–32.04) | 730 | 34.56 (24.50–48.75) | 116 | 3.62 (1.71–7.64) |
| ≥ 90 | 457 | 65.85 (44.56–97.30) | 404 | 108.09 (70.69–165.27) | 57 | 4.69 (1.75–12.54) |
| Season | ||||||
| March–May | 1350 | 1 (ref) | 1182 | 1 (ref) | 185 | 1 (ref) |
| June–August | 1339 | 0.99 (0.92–1.07) | 1134 | 0.96 (0.88–1.04) | 222 | 1.20 (0.99–1.46) |
| September–November | 1337 | 1.02 (0.94–1.11) | 1149 | 1.00 (0.92–1.09) | 210 | 1.23 (1.00–1.52) |
| December–February | 1353 | 1.05 (0.98–1.14) | 1162 | 1.03 (0.95–1.12) | 205 | 1.19 (0.97–1.45) |
Abbreviations: CI, confidence interval; IRR, incidence rate ratio.
Tables S1 and S2 present the results of the subgroup analyses. Similar results were observed for both women and men. However, the adjusted IRR for risk period 1 for outcomes based on neurological diseases other than epilepsy could not be estimated, probably because of the limited number of outcomes in the subgroup analysis of men. All the sensitivity analyses yielded results similar to those of the main analyses (Tables S3–S6).
4. Discussion
In this study, we examined the risk of adverse neurological events after influenza vaccination using a large claim database and vaccination records via SCCS analysis. SCCS analyses demonstrated no significant increase in the risk of hospitalization for neurological diseases after influenza vaccination in older adults aged ≥ 65 years. This pattern was consistent across subgroup analyses by sex, and the sensitivity analyses confirmed the robustness of the results.
The risk of neurological disorders from influenza vaccination, which extends beyond older adults, has been previously explored. A large database study in Sweden utilized the SCCS method to assess the risk of epilepsy from influenza vaccination and found no increase in the risk [13]. Our findings regarding epilepsy are consistent with those reported in the Swedish study. Another self‐controlled study in Canada reported an increased risk of Guillain–Barre syndrome after vaccination [12]. However, their subgroup analysis focusing on older adults identified no apparent increase in the risk. Thus, our findings regarding neurological outcomes other than epilepsy are still consistent with the Canadian study.
By contrast, a cohort study using a large Swedish healthcare database identified an increased risk of developing Bell's palsy among the vaccinated group compared with that among the nonvaccinated group of influenza vaccine recipients [11]. This contrasts with our study's findings, which focused on neurological diseases other than epilepsy despite the different definitions of outcomes. Several factors may have contributed to this discrepancy in results. The cohort study was conducted in another country, which included a broader target population and was not restricted to older adults. Although they adjusted for several covariates, such as sex, age, and socioeconomic status, concerns about the influence of unmeasured or unadjusted confounders remain. By contrast, this study employed an SCCS‐based analysis that automatically adjusted for time‐invariant confounders under certain assumptions. These differences may explain the different results obtained.
This study had some limitations. First, the link between injury/illness and hospitalization remains unclear. Although medical treatment and hospitalization were linked based on matching claim identifiers and recorded months, this may not have fully confirmed the correspondence. Second, hospitalizations with neurological diseases occurring at short intervals were treated as a series of episodes, resulting in a period after each outcome occurrence, where no outcome could occur. This may have underestimated the risk during this period. Third, our analyses ignored yearly changes in influenza vaccination composition. Fourth, our analysis used data from a specific municipality in Japan. Although the SCCS design mitigated the impact of time‐invariant covariates to some extent, it remains uncertain whether these findings can be extrapolated to older adults in other areas.
5. Conclusions
In conclusion, this study found no apparent increase in the risk of neurological adverse events following influenza vaccination in older adults. These results may alleviate concerns among older adults who are hesitant to receive influenza vaccination owing to the fear of adverse neurological outcomes. However, further large‐scale studies are required to confirm the safety of influenza vaccination in older adults.
5.1. Plain Language Summary
Adverse neurological risks following influenza vaccination in older adults have not yet been sufficiently assessed. Using a linked database containing healthcare administrative claims data and vaccination records from an urban city in Japan (April 1, 2014, to March 31, 2020), we compared the risk of hospitalizations related to neurological diseases during post‐vaccination periods (0–6 days and 7–29 days after each vaccination) with those during nonvaccination periods in older adults. We found no evidence that the risk of adverse neurological events was increased after influenza vaccination in older adults. These results may help reassure older adults who are hesitant to receive influenza vaccination because of concerns regarding adverse neurological outcome.
Author Contributions
M. Ogawa contributed to conceptualization, design, analysis, interpretation of the study, and writing – original draft. Y. Takeuchi and M. Iwagami contributed to conceptualization, design and interpretation of the study. Y. Iida contributed to conceptualization, design, analysis, and interpretation of the study. K. Uemura, S. Ono, N. Michihata, D. Koide, and Y. Matsuyama contributed to interpretation of the study. H. Yasunaga contributed to data acquisition and interpretation of the study. All authors contributed to writing – review and editing and gave final approval of the manuscript.
Ethics Statement
This study was approved by the Research Ethics Committee, Graduate School of Medicine and Faculty of Medicine, the University of Tokyo (approval no. 2021187NI‐(3)). Given that our analyses involved the secondary use of anonymized data routinely collected by the local government in Japan, the need for individual informed consent was waived in accordance with the current ethical guidelines for medical and health research involving human participants in Japan.
Conflicts of Interest
Y.T. had received consultant fees from Pharmaceuticals and Medical Devices Agency, EPARK Inc. and EPS Corporation. Y.T. has been conducting a collaborative study with Pfizer Inc. which is not related to this study. The remaining authors declare no conflicts of interest.
Supporting information
Data S1.
Acknowledgments
We would like to thank Editage (www.editage.com) for editing the English language.
Funding: This research was supported by Japan Agency for Medical Research and Development (AMED) under grant numbers: JP21nf0101636 and JP21lk0201701. The funding source has no role in data analysis, interpretation, and writing of the manuscript.
Data Availability Statement
The database used in this study is maintained by City A of Japan. Restrictions apply to data availability, which was used with permission for this study. Thus, these data are not publicly available.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Data S1.
Data Availability Statement
The database used in this study is maintained by City A of Japan. Restrictions apply to data availability, which was used with permission for this study. Thus, these data are not publicly available.