| Cohort study design |
| Cohort study with historical comparison group, also called current vs historical design | Individual vaccinated with the vaccine of interest | Historical incidence rate of AEFIs calculated from historical data on individuals that have not been exposed to the vaccine of interest
vs
Incidence of AEFIs in the prespecified risk period/window following vaccination | It has greater statistical power to detect rare AEFIs signal earlier It is less affected by data lags as it only collects for the risk window, rather than both for risk and comparison windows
| Highly dependent on accurate estimation of background incidence rates of the AEFIs for comparison It may be subjected to difference in confounders between current and historical vacinees, seasonality and secular trends in AEFIs, diagnostic or coding criteria
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| Cohort study with concurrent/parallel comparison group (matched or not) | Individual vaccinated with the vaccine of interest | Incidence of AEFIs in the prespecified risk period/window following vaccination
vs
Incidence of AEFIs among individuals without the vaccine of interest or totally non vaccinated individuals | | Difficult to get adequate number of unvaccinated control group, in case of studying routinely administered vaccines May be subjected to bias due to difference in characteristics of vaccinated and unvaccinated groups For a rare AE, it may not provide the earliest possible signal
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| Self-controlled design |
| SCRI | Vaccinated cases | Within subject comparison Incidence of AEs in the predefined risk period following vaccinations vs Incidence of AEFIs in the predefined control/non risk period
| Automatically control time-invariant confounders that vary between individual, such as sex, socioeconomic status Less prone to misclassification of exposure, vaccinated cases are considered to collect information Compare the risk of AEFIs in the short control interval where time variables (such as age) have minimal effect in the study period.
| Has less statistical power due to fewer events occurring in the shorter control interval Less suitable to capture subacute or chronic AEFIs for example, autoimmune disease Confounded by indication It is not free from bias due to time-varying confounders for example, Age and seasonality Selecting a risk interval that is too wide or too short may bias the risk estimate relative to the true risk window. Sensitive to indication bias
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| SCCS | Primarily vaccinated persons, but unvaccinated persons and experienced the AEs can be considered | Within subject comparison Incidence of AEFIs in the predefined risk period following vaccinations vs Incidence of AEFIs in the control period (time period before or after vaccination)
| | Less suitable to capture subacute or chronic AEFIs More susceptible to bias because of time-varying confounders, as the observation period is often longer than SCRI Problem with defining risk interval (selecting a risk interval that is too wide or too short may bias the risk estimate relative to the true risk window). Sensitive to indication bias
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| Case-crossover design | All individuals who are vaccinated and cases | Subjects serve as their own matched controls with defined by prior time periods in the same subject | | Does not address confounders that vary over time Susceptible to exposure trend bias for example, due to change in policy for a vaccine Sensitive to indication bias
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