Risk of stroke within 3, 7, 14, 21 and 30 days after influenza vaccination in Alberta, Canada: A population‐based study

Abstract

Background and purpose

Influenza vaccination is associated with a longer‐term protective effect against stroke; however, it has a short‐term inflammatory response which may increase short‐term risk of stroke. The aim was to investigate the association between influenza vaccination and short‐term risk of stroke in adults.

Methods

Administrative data were obtained from the Alberta Health Care Insurance Plan for all adults in Alberta, Canada, from September 2009 to December 2018. The hazard of any stroke (acute ischaemic stroke, intracerebral haemorrhage, subarachnoid haemorrhage and transient ischaemic attack) within 3, 7, 14, 21 and 30 days of influenza vaccination compared to unexposed time was analysed using Andersen−Gill Cox models, with adjustment for age, sex, anticoagulant use, atrial fibrillation, chronic obstructive pulmonary disease, diabetes, hypertension, income quintile, and rural or urban home location.

Results

In the entire cohort consisting of 4,141,209 adults (29,687,899 person‐years), 1,769,565 (42.7%) individuals received at least one vaccination. In total 38,126 stroke events were recorded with 1309 occurring within 30 days of a vaccination event. Influenza vaccination was associated with a significantly reduced hazard of stroke within 3 days (hazard ratio [HR] 0.83, 95% confidence interval [CI] 0.73–0.93), 7 days (HR 0.87, 95% CI 0.80–0.95), 14 days (HR 0.87, 95% CI 0.81–0.93), 21 days (HR 0.85, 95% CI 0.80–0.91) and 30 days (HR 0.66, 95% CI 0.65–0.68).

Conclusions

An increased early risk associated with vaccination was not observed. The risk of stroke was reduced at all time points within 30 days after influenza vaccination.

INTRODUCTION

Infectious diseases such as influenza infection increase the risk of stroke [1, 2]. Influenza vaccination causes a short‐term inflammatory response which may result in adverse effects such as headache, malaise and hyperhidrosis in the week following vaccination. Serious adverse effects of influenza vaccination are rare [3]. Whilst influenza vaccination is associated with a reduced risk of stroke in the 6 months after vaccination (hazard ratio [HR] 0.78, 95% confidence interval [CI] 0.76–0.79) [4], the short‐term inflammatory response could paradoxically be associated with a slight increase in stroke risk. Previous studies suggested that influenza vaccination was associated with reduced incidence of stroke very shortly (1–3 days) after vaccination [5, 6]. However, these results were from within‐person comparisons and the short‐term risk of stroke in the entire population was still unclear.

By analogy to another respiratory viral infection, COVID‐19 vaccination was shown to increase the risk of stroke within 21 days after vaccination in one study [7], although this finding was not consistent with a second study [8]. It was hypothesized that there may be a biphasic response to vaccination with early harm and later protection. Therefore, the aim was to investigate the risk of a stroke shortly after influenza vaccination, using several early time frames, using population‐level data from all adult individuals of Alberta, Canada.

METHODS

Study design and data source

The methodology of this study is similar to that previously described [4]. Population‐level data were obtained from all adult individuals registered under the Alberta Health Care Insurance Plan from 30 September 2009 to 31 December 2018.

Individuals entered the cohort on the latest of two dates: 30 September 2009 or 15 May of the year in which they were recorded as being 18 years of age. Individuals were censored at the earliest of three events: death, recorded outmigration or 31 December 2018. This study was approved by the Conjoint Health Research Ethics Board at the University of Calgary. Informed consent was not required because of the anonymised nature of the study.

Exposure, outcomes and covariates of interest

The exposure of interest was the recent seasonal influenza vaccination defined as the 3‐, 7‐, 14‐, 21‐ and 30‐day time windows post vaccination. Seasonal influenza vaccinations are provided by the province, at no charge to individuals, and all vaccination events are recorded in the Immunization and Adverse Reaction to Immunization Registry.

The outcome of interest was any stroke (acute ischaemic stroke, intracerebral haemorrhage, subarachnoid haemorrhage and transient ischaemic attack). Outcome events were identified using the Morbidity and Ambulatory Care Abstract Reporting System by identifying validated International Classification of Diseases, tenth edition codes in the main diagnostic position.

Patient‐level covariates of interest included age (determined at the cohort midpoint of 15 May 2014), sex, rural or urban home location (defined using postal codes), a prescription for anticoagulant medication, and the following comorbidities: atrial fibrillation, chronic obstructive pulmonary disease, diabetes and hypertension. The quintile of median neighbourhood income (dichotomized into top quintile vs. all others), an ecological variable, was assigned to patients according to their home neighbourhood. Covariates were identified using linked data from the Alberta Health Care Insurance Plan, the Morbidity and Ambulatory Care Abstract Reporting System and the Canadian Census (years 2011 and 2016). All case definitions are provided in the Supplementary Methods S1.

Statistical analysis

All statistical analyses were performed using Stata version 18 (Stata Corp.). Andersen−Gill Cox models with robust variance estimators were used to analyse the hazard of any stroke for individuals recently exposed to the seasonal influenza vaccination compared with unexposed time. The analysis was performed by excluding cases with missing variables. Additional analysis was performed by stroke type. A p value <0.05 was considered significant for all tests. Detailed statistical methods are provided in the Supplementary Methods S1.

RESULTS

Details of cohort flow and baseline characteristics of this cohort are shown in Figure S1 and Table S1. The analysis population consisted of 4,141,209 adult individuals with a total observation time of 29,687,899 person‐years of follow‐up. Over the study period, 1,769,565 (42.7%) individuals received at least one influenza vaccination. Individuals who received at least one influenza vaccination were older (mean 48.4 years vs. 39.0 years at the cohort midpoint), consisted of a higher proportion of women (56.0% vs. 44.4%) and had higher rates of comorbidities than the group of individuals who had never received an influenza vaccination (hypertension 13.4% vs. 7.7%; diabetes 6.7% vs. 3.3%; chronic obstructive pulmonary disease 4.1% vs. 1.5%; and atrial fibrillation 2.1% vs. 0.7%). The proportion of individuals living in urban areas was slightly higher in the vaccinated group (80.9% vs. 77.9%); however, the proportion of individuals in the highest income quintile was similar across both groups (19.0% vs. 20.1%).

Amongst 38,126 recorded stroke events, 1309 occurred within 30 days of a vaccination event. The crude incidence of any stroke was higher amongst individuals who had ever received an influenza vaccination (1.3%) compared with those who had not (0.5%). Adjusted for age, sex, comorbid illness and markers of socioeconomic status, recent vaccination was associated with a reduced hazard of stroke within 3 days (HR 0.83, 95% CI 0.73–0.93), 7 days (HR 0.87, 95% CI 0.80–0.95), 14 days (HR 0.87, 95% CI 0.81–0.93), 21 days (HR 0.85, 95% CI 0.80–0.91) and 30 days (HR 0.66, 95% CI 0.65–0.68) (Table 1). Additional analysis showed this risk reduction was driven by acute ischaemic stroke, with no evidence of harm amongst stroke types (Table S2).

TABLE 1.

Adjusted hazard ratios and 95% confidence intervals for stroke after influenza vaccination.

Time frames	Number of events	HR (95% CI) a
Within 3 days	284	0.83 (0.73–0.93)
Within 7 days	601	0.87 (0.80–0.95)
Within 14 days	905	0.87 (0.81–0.93)
Within 21 days	1286	0.85 (0.80–0.91)
Within 30 days	16,004	0.66 (0.65–0.68)

Note: Time windows are not mutually exclusive.

Abbreviations: CI, confidence interval; HR, hazard ratio.

^a Adjusted for age, sex, atrial fibrillation, chronic obstructive pulmonary disease, diabetes, hypertension, home location and income quintile.

DISCUSSION

In this study, a biphasic response to influenza vaccination and risk of stroke was not observed; influenza vaccination was associated with a reduction in the hazard of stroke in the short time window following vaccination and this effect was driven by acute ischaemic stroke. The protective effect evolved over time with the greatest magnitude observed using the 30‐day time window (HR 0.66). At 6 months, the effect was slightly attenuated (HR 0.78) [4]. This trend was similar to a previous population‐based case–control study which also found a stronger protective effect for the outcome of first stroke in the early period (15–30 days, odds ratio 0.79) which declined over time (>150 days, odds ratio 0.92) [9]. Our results were consistent with results from the recent nationwide study showing no associations between vaccination including an influenza vaccine and hospitalization due to multiple sclerosis flare‐ups within 60 days after vaccination [10].

A significant risk reduction was seen in the 3‐day period after vaccination, similar to previous reports [5, 6]. Biologically, this is unlikely to be due to the protective effective of the influenza vaccination itself, as it takes approximately 2 weeks to develop an immune response from vaccines [11]. One possible reason is that individuals are more likely to receive vaccinations when they are feeling well, whereas individuals with prodromal symptoms of stroke or at immediate high risk of stroke may have withheld vaccination. This healthy vaccine recipient effect might account for some or all of the early protective effect seen in this analysis. Further, it may imply that the 30‐day and 6‐month benefit is a summative estimate of effect composed of both an observed effect associated with vaccine‐seeking behaviour plus the true biological benefit of vaccination.

This study utilized entire population data from a single payer healthcare system, removing the risk of sampling bias and mitigating the risk of misclassification of the exposure or outcome. However, there is the potential for a 2‐day delay from vaccination to registration of vaccination, particularly on weekends, which may have impacted our vaccination exposure classification in the very short term. Residual confounding remains possible because many risk factors, for example lifestyle factors such as smoking, are not recorded in administrative data. The biological effect of the influenza vaccine and the act of being vaccinated cannot be distinguished. Although it is biologically plausible that the influenza vaccine might be associated with reduced stroke risk, it is also plausible that individuals seeking seasonal immunizations have higher health literacy and perhaps healthier lifestyles, leading to an inherent reduced stroke risk. Further analysis with mutually exclusive time windows, excluding a period immediately prior to vaccination or wash‐out period after the risk interval, could minimize the residual risk attributable to the vaccine or help to explore the healthy vaccine recipient effect. The yearly makeup of influenza vaccine and some possible confounders (e.g., history of stroke or other treatments) were not included due to the difficulty in identifying from the administrative dataset. The rate of vaccination in this study was comparable to that in all Canada or the United States [12, 13] but was lower than a target vaccination rate of 70% from the Healthy People 2020 [14].

In summary, it has been shown that there is no evidence of harm due to the postulated inflammatory response induced by influenza vaccination. Significant protective effects across all time categories suggest that broad influenza vaccination is a potentially viable public health strategy to reduce the risk of stroke.

AUTHOR CONTRIBUTIONS

Koji Tanaka: Writing – original draft; conceptualization; investigation. Andrew M. Demchuk: Conceptualization; writing – review and editing; supervision; investigation. Shaun Malo: Writing – review and editing; data curation. Michael D. Hill: Writing – review and editing; formal analysis; investigation. Jessalyn K. Holodinsky: Writing – original draft; investigation; formal analysis; methodology.

FUNDING INFORMATION.

None.

CONFLICT OF INTEREST STATEMENT

The authors report no conflicts of interest.

DISCLOSURES

Outside of the current work, MDH reports grants from Biogen, Medtronic, Boehringer Ingelheim, NoNO, the Canadian Institutes for Health Research, and Alberta Innovates; consulting fees from Sun Pharma Brainsgate; US patents 62/086077 and 10,916,346 licensed to Circle NVI; data safety monitoring board roles in the RACECAT trial (Chair, ended 2020), Oncovir Hiltonel trial (Chair, ongoing), DUMAS trial (Chair, ongoing), ARTESIA trial (member, ongoing) and BRAIN‐AF trial (member, ongoing); leadership roles in the Canadian Neurological Sciences Federation (President, not for profit) and the Canadian Stroke Consortium (board member, not for profit); and stock ownership in Circle and PureWeb. JKH reports funding from the Canadian Institutes of Health Research. All other authors declare no competing interests.

Supporting information

Appendix S1:

Tanaka K, Demchuk AM, Malo S, Hill MD, Holodinsky JK. Risk of stroke within 3, 7, 14, 21 and 30 days after influenza vaccination in Alberta, Canada: A population‐based study. Eur J Neurol. 2024;31:e16172. doi: 10.1111/ene.16172

DATA AVAILABLITY STATEMENT

Due to the nature of this research using administrative data across a population, participants of this study did not agree for their data to be shared publicly, so supporting data are not publicly available.