Highlight
- WHO recommends two influenza vaccine doses for vaccine-naive children under 9 based on immunogenicity evidence.
- The meta-analysis shows a 28 percentage point increase in vaccine effectiveness with two doses in children under 3 years old.
- For children under 9, the additional protection from a second inactivated vaccine dose was 15 percentage points but did not reach statistical significance.
- There is insufficient evidence on incremental benefits of second doses for live attenuated influenza vaccines, indicating a need for further high-quality studies.
Study Background and Disease Burden
Seasonal influenza remains a significant cause of morbidity in pediatric populations worldwide, leading to substantial outpatient visits, hospitalizations, and, in severe cases, mortality. Young children, particularly those under five years, are at heightened risk for complications. The World Health Organization (WHO) has advised that influenza vaccine-naive children younger than 9 years should receive two doses of the influenza vaccine in their first vaccination season to enhance immunologic response and protection. However, the precise clinical effectiveness gain from the second dose, especially across different age brackets and vaccine types, has not been systematically quantified to inform policy refinement.
Study Design
A rigorous systematic review and meta-analysis were conducted by Goldsmith et al., including 51 peer-reviewed studies encompassing 415,050 children aged 6 months to under 9 years who were influenza vaccine-naive at baseline. The literature search spanned MEDLINE, EMBASE, and CINAHL databases up to March 24, 2025. Included studies reported vaccine efficacy (VE) or vaccine effectiveness (VEff) stratified by the number of doses received in the first vaccination season. Excluded were modeling studies and economic evaluations. Two independent reviewers screened and extracted data and assessed risk of bias using established criteria, adhering to PRISMA guidelines.
The analysis separated outcomes for inactivated influenza vaccines (IIV) and live attenuated influenza vaccines (LAIV). The main outcome measure was the absolute difference in VE or VEff between one dose and two doses in influenza vaccine-naive children during their first vaccinated season.
Key Findings
The pooled data revealed that two doses of inactivated influenza vaccine conferred an absolute increase in vaccine effectiveness of 15 percentage points (95% CI, -2.8 to 33) among children younger than 9 years, though this effect did not reach statistical significance across the whole age range. When the analysis focused on the subgroup of children younger than 3 years, the benefit conferred by a second IIV dose was substantially greater and statistically significant, with a 28 percentage point increase in vaccine effectiveness (95% CI, 4.7 to 51).
Data on the live attenuated influenza vaccine were limited and insufficient to robustly estimate the incremental benefit of a second dose. Safety data were not the primary focus but were generally consistent with established vaccine profiles, with no new safety signals reported.
The findings underscore that the immunologic rationale for two doses translates into meaningful incremental protection predominantly in the youngest children, with diminishing measurable benefit as children approach 9 years of age.
Expert Commentary
This comprehensive meta-analysis provides valuable evidence supporting current WHO recommendations for administering two doses of influenza vaccine to vaccine-naive children, particularly emphasizing children under 3 years. The modest and statistically nonsignificant benefit in older children within the under-9 cohort suggests that age-stratified approaches could optimize vaccine policy and resource allocation.
Limitations of the evidence include heterogeneity in study designs, variable influenza seasons, and differences in circulating strains, which may influence observed vaccine effectiveness. The lack of sufficient data on live attenuated vaccines highlights a critical research gap. Furthermore, the analysis did not include immunogenicity data directly but relied on effectiveness endpoints, which are more clinically meaningful.
Current pediatric influenza vaccine guidelines might benefit from refinement to consider more nuanced age stratification and vaccine type-specific recommendations. High-quality prospective studies are needed to establish these parameters robustly.
Conclusion
The systematic review and meta-analysis demonstrate that two doses of inactivated influenza vaccine significantly improve protection against influenza among vaccine-naive children younger than 3 years during their first vaccination season. For children aged 3 to under 9 years, the added clinical benefit of a second dose is less certain and did not achieve statistical significance based on the current pooled data. Evidence for live attenuated influenza vaccines remains insufficient.
These findings reinforce vaccination policy recommending two doses for the youngest children, while highlighting the need for further definitive research across broader age ranges and vaccine formulations. Clinicians should continue to follow existing guidelines, recognizing that individual patient factors and local epidemiology may influence vaccination strategies.
References
Goldsmith JJ, Tavlian S, Vu C, Regan AK, Campbell PT, Sullivan SG. Comparison of 2 Doses vs 1 Dose in the First Season Children Are Vaccinated Against Influenza: A Systematic Review and Meta-Analysis. JAMA Netw Open. 2025 Oct 1;8(10):e2535250. doi: 10.1001/jamanetworkopen.2025.35250. PMID: 41042511.