Effectiveness of COVID-19 Vaccine Boosters in Children Across Pandemic and Endemic Periods.

In the SARS-CoV-2 endemic phase, assessing the effectiveness of COVID-19 booster doses in children is essential for public health policy. This study evaluated the vaccine effectiveness (VE) of three doses (primary series plus booster) against severe outcomes, comparing the pandemic and endemic periods and children with and without comorbidities. We carried out a cohort study based on the population, utilizing comprehensive Brazilian data from individuals under 18 years of age with confirmed SARS-CoV-2 infection, spanning from February 2020 to June 2025. The primary exposure of interest was three or more doses of COVID-19 vaccines. The primary outcome of interest was COVID-19-related death. VE and the number needed to vaccinate (NNV) to prevent one death were estimated in a propensity score-matched cohort, with adjustments for confounders. Among 3,730,007 reported pediatric cases, 5472 (0.1%) died, 99% of whom did not receive a booster dose. During the pandemic, the VE against death was higher in children with comorbidities (92.7% [95% CI, 63.5-99.0]; NNV = 23 [19-30]) than in those without (68.2% [25.7-86.4]; NNV = 2000 [1111-9774]). During the endemic period, the VE against death remained high and was comparable between groups: 89.4% (29.8-98.7) and 75.8% (36.4-95.7) for children with and without comorbidities, respectively. Nevertheless, NNV levels were significantly lower in children with comorbidities, reflecting an increased risk at baseline. Although booster doses continue to offer substantial protection against fatal COVID-19 outcomes, the magnitude of this benefit is directly correlated with the baseline risk. Consequently, these findings support the implementation of risk-based prioritization strategies in public health decision-making for children.