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Can We Compare Adverse Event's Attributable Risk Using a Self-Controlled Case Series Design for Vaccine Safety? A
Caihua Liang1, Erica L Chilson2, Joanne Wu2
1Pfizer Inc., New York/Collegeville, USA. caihua.liang@pfizer.com.
Infectious Diseases and Therapy
|August 7, 2026
Summary
Self-controlled case series (SCCS) analyses for vaccine safety may overestimate attributable risk (AR). Standardizing AR calculations using population-based background rates provides a more accurate estimate of vaccine-specific risks like Guillain-Barré syndrome (GBS).
Area of Science:
- Vaccinology
- Epidemiology
- Biostatistics
Background:
- Self-controlled case series (SCCS) analyses are used to estimate vaccine safety but may lack generalizability.
- SCCS analyses may overestimate attributable risk (AR) for adverse events like Guillain-Barré syndrome (GBS) by using only vaccinated individuals with the outcome.
Purpose of the Study:
- To assess the impact of background event incidence rates on vaccine-specific GBS ARs.
- To standardize AR calculations across vaccine studies using a generalizable, population-based GBS background rate.
Main Methods:
- Identified post-licensure SCCS vaccine studies and GBS background rates from US Medicare data.
- Calculated population-level ARs for vaccines using SCCS-derived incidence rate ratios (IRRs) and various background GBS rates.
Main Results:
- Vaccine-specific GBS incidence rate ratios (IRRs) varied, with RSVpreF at 2.02 and recombinant zoster vaccine (RZV) at 4.96.
- Study-specific ARs per 100,000 doses ranged from 0.28 (H1N1) to 0.90 (RSVpreF).
- Standardized ARs using external background rates showed higher values for vaccines with higher IRRs, e.g., RZV at 2.26 per 100,000 doses.
Conclusions:
- Attributable risk (AR) calculations are sensitive to the control period event rate used in SCCS analyses.
- Exclusive reliance on SCCS-derived ARs may lead to inaccurate conclusions about absolute risk due to limited external validity.
- Employing a representative background rate alongside SCCS-derived IRRs offers a consistent method for calculating population-level ARs, supporting vaccine risk-benefit assessments.
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