Background Incidence Rates of Selected Vaccine Adverse Events of Special Interest in Canada

Study type

• Study topic:
  Disease /health condition
• Study type:
  Non-interventional study
• Scope of the study:
  Disease epidemiology
• Data collection methods:
  Secondary use of data

Non-interventional study

• Non-interventional study design:
  Cohort

Study drug and medical condition

• Additional medical condition(s):
  Vaccine adverse events of special interest (AESIs)

Population studied

• Short description of the study population:
  The study population will consist of all individuals who were registered for provincial medical services coverage between January 1, 2015, and December 31, 2024 (or the latest date of data availability in each province).
• Age groups:
  • Paediatric Population (< 18 years)

    • Neonate

      • Preterm newborn infants (0 – 27 days)
      • Term newborn infants (0 – 27 days)
    • Infants and toddlers (28 days – 23 months)
    • Children (2 to < 12 years)
    • Adolescents (12 to < 18 years)
  • Adult and elderly population (≥18 years)

    • Adults (18 to < 65 years)

      • Adults (18 to < 46 years)
      • Adults (46 to < 65 years)
    • Elderly (≥ 65 years)

      • Adults (65 to < 75 years)
      • Adults (75 to < 85 years)
      • Adults (85 years and over)

Study design details

• Study design:
  Federated, multi-jurisdictional descriptive retrospective cohort study
• Main study objective:
  This study is a replication of the previous DARWIN EU study (EUPAS1000000254) using data from 6 Canadian provinces. The study has 3 primary objectives:; ; 1. To estimate population level incidence rates of selected AESIs in the general population during 2015 and until the latest data availability, overall and stratified by calendar period based on COVID-19 (pre-, during- and post-pandemic periods), calendar quarter, sex, age groups, sex and age groups, and province.; ; 2. To estimate age and sex standardized incidence rates (to the Canadian and European population) of the selected AESIs in the general population during 2015 and until the latest data availability, stratified by calendar period based on COVID-19 pre-, during- and post-pandemic periods, calendar quarter, sex, and province.; ; 3. To describe the demographic and clinical characteristics of individuals with incident AESIs and compare these with individuals without the AESIs matched on age, sex and calendar time of the event.
• Setting:
  The analysis will be conducted separately in pediatric and adult populations. Due to data availability, Alberta will contribute only to the adult cohort. In each case, the study population will consist of all individuals in that age group who were registered for provincial medical services coverage at any time in the study period, defined as January 1, 2015, to December 31, 2024 (or the latest date of data availability in each province). A minimum lookback period (continuous health plan enrollment) of 365 days will be required to ensure adequate capture of incident AESIs events and measurement of covariates.; ; Incidence of AESIs will be estimated overall and within calendar periods (annual and quarterly). Individuals will be eligible to contribute person-time to the at-risk population for each AESI provided that they have no prior record of that specific outcome within a prior 365-day washout window. For each outcome, follow-up (cohort entry) will begin on the latest of: the study start date (January 1, 2015), the date on which individuals have sufficient prior data availability (365 days), or the date on which they fulfil the 365-day washout window. Individuals will be followed up until the earliest of: occurrence of the AESI (event date), death, loss of provincial coverage, the day of exceeding the specified age range (in age-group specific analysis), or the end of the study period (December 31, 2024, or the latest date of data availability). Individuals will be allowed to enter the outcome-specific cohort multiple time provided they meet all the eligibility criteria.
• Comparators:
  Not applicable
• Outcomes:
  We will assess the incidence of 5 AESI categories evaluated in the DARWIN EU study: Guillain-Barré Syndrome, myocarditis, encephalitis, stroke, and thrombocytopenia. In the primary analysis, outcomes will be defined using inpatient and emergency department (where available) data only. In provinces with access only to inpatient data, outcomes will be defined using those data. Where feasible, outcomes will be defined using both broad and narrow case definitions.
• Data analysis plan:
  In each province, the incidence rate for each AESI will be calculated as the number of cases per 100,000 person-years at risk during the study entire study period, excluding the COVID-19 pandemic period, in order to avoid its influence on the baseline rates of these outcomes, and 95% confidence intervals will be estimated using the Poisson distribution. Using data from the same period as the overall rates, incidence rates will be stratified by the following subgroups: calendar year, calendar quarter, time period relative the COVID-19 pandemic (pre-: 2015-2019; during: 2020-2022; and post-: 2023 to latest available data), sex, age group (pediatric cohort: 0-12 and 13-17; adult cohort: 18-29, 30-39, and so on to ≥ 80 years), and sex and age group. All incidence rates will be further age and sex standardized to the Canadian and European populations by the direct method.; ; For each incident AESI cohort, demographic and clinical characteristics of cases will be summarized. To contextualize these characteristics, each case will be matched 1:1 to individuals without the AESIs on age, sex, and calendar time of the event. Characteristics between the AESI and matched cohorts will be compared using standardized mean differences.; ; Three sensitivity analyses will be conducted. First, as in the DARWIN EU study, different case definitions for selected AESIs (encephalitis and ischemic stroke) will be applied to assess the impact of varying sensitivity and specificity. Second, rates will be estimated in Manitoba and Ontario using data only from the post-pandemic period, as this may better represent the current baseline rates of these AESIs. Third, a 90-day washout window for AESIs will be used in Manitoba and Ontario for closer alignment with the DARWIN EU study. If necessary, these sensitivity analyses will be conducted in the remaining provinces.; ; Results will be reported for each province separately and pooled using random-effects meta-analyses to provide national baseline rates.