Approaches to observational study designs and analytical options to evaluate the safety of multi-dose vaccines: a systematic review.

INTRODUCTION

Observational studies require careful considerations when evaluating the safety of multidose vaccines. We reviewed design and analytical approaches in observational studies evaluating the safety of multidose vaccines in the post-licensure phase.

METHODS

EMBASE, MEDLINE, Web of Science, and Scopus (2018-2022) were searched for hypothesis-testing studies evaluating the safety of multidose vaccines. Key features from frequently used designs were extracted.

RESULTS

Among 123 eligible studies, cohort (46%) and self-controlled case series (SCCS)/self-controlled risk interval (SCRI) (40%) followed by case-control (12%) were the most common designs, and 15% of studies used multiple designs. Among cohort studies evaluating multiple doses, vaccination date (36%) and cohort entry with time-updated exposure status (32%) were frequent approaches used to define time zero. Twenty-eight percent of cohort studies did not report time zero; all but one evaluated COVID-19 vaccine effect on post-delivery and fertility-related outcomes. For SCCS/SCRI, 64% of studies accounted for event-dependent exposures, mainly by including pre-exposure periods (53%) and modified SCCS model (48%), while 20% employed multiple correction strategies. Among studies using multiple designs, 68% reached consistent conclusions.

CONCLUSIONS

SCCS/SCRI and cohort designs dominate multidose vaccine safety studies. Clear reporting on time zero in pregnancy and fertility-related cohort studies, and on addressing event-dependent exposures in SCCS/SCRI studies is needed, along with guidance on interpreting results from multiple designs.