Mapping Pediatric Seasonal Influenza Vaccine Safety and Immunogenicity Evidence: A Systematic Review of Clinical...

Background: Influenza poses a significant health threat to children under nine, who are at high risk of severe complications. Influenza vaccination is a key prevention strategy, but pediatric trials use heterogeneous safety and immunogenicity outcomes, follow-up windows, and dosing strata that hinder meaningful cross-trial comparison. Objective: To map how safety and immunogenicity outcomes are defined, collected, stratified, and reported across clinical trials of seasonal influenza vaccines in healthy children aged 6 months to 8 years, and to identify reporting patterns and gaps that limit cross-trial comparability. Methods: Studies were identified through a structured PubMed/MEDLINE search first conducted 20 April 2025 and last conducted June 2025, following JBI and PRISMA 2020 guidelines. We included clinical trials reporting at least one safety outcome in healthy children 6 months to 8 years old. Heterogeneity in outcome definitions, follow-up windows, and dose strata precluded meta-analysis; we conducted a narrative and per-study synthesis. Risk of bias was evaluated with RoB 2 for randomized trials and ROBINS-I (V2) for non-randomized studies following Cochrane guidance. Descriptive and visual syntheses were utilized. Results: Of 293 records, 20 studies comprising approximately [n = 12,267] pediatric participants met the inclusion criteria. All included studies evaluated inactivated, egg-based seasonal influenza intramuscular vaccines. Reporting windows and dose handling varied widely. Vaccine-related serious adverse events (SAEs) were rare (only four events, with reported SAEs happening in children 6-35 months old immunized with quadrivalent formulations; all SAEs resolved and did not result in participant withdrawal from the study). No SAEs were reported in children 3-8 years old. Immunogenicity outcomes are presented as reported by each trial, with baseline and post-vaccination sampling days reproduced; no cross-trial synthesis was performed. Conclusions: Seasonal, inactivated intramuscular influenza vaccines show a favorable safety and immunogenicity profile in healthy children 6 months to 8 years old. However, heterogeneous outcome definitions, variable safety follow-up windows, limited dose- and priming-specific reporting, and inconsistent immunogenicity schedules substantially constrain cross-trial comparability. Funding and Registration: Primary funding was provided by the Eunice Kennedy Shriver National Institute of Child Health and Human Development (Grant HD109732). This review was registered in PROSPERO (registration number: CRD420251237499).