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PubMed · 42057741

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

Monica Mtei·Tu Pham Hien Trang·Adoración Navarro-Torné·Ian J Douglas·Anna Schultze
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Abstract

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.

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HumansObservational Studies as TopicResearch DesignVaccinesCOVID-19 VaccinesVaccinationCase-controlcohortobservational study designspost-licensure vaccine safetyself-controlledsystematic reviewvaccine safetyJournal ArticleSystematic Review

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Monica Mtei, Tu Pham Hien Trang, Adoración Navarro-Torné, Ian J Douglas, Anna Schultze. 2026-05-18. Approaches to observational study designs and analytical options to evaluate the safety of multi-dose vaccines: a systematic review.. https://doi.org/10.1080/14760584.2026.2667740

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Journal Article; Systematic Review resourceCOVID-19 Vaccines subjectCase-control subjectHumans subjectJournal Article subjectObservational Studies as Topic subjectSystematic reviews studycohort subjectobservational study designs subject

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