Impact of Prior SARS-CoV-2 Infection on COVID-19 Vaccine Effectiveness in Children and Adolescents in Norway and Italy

<b>Background and objective</b>: The approval of mRNA-based vaccines for children and adolescents has contributed to global efforts to control the SARS-CoV-2 pandemic. While hybrid immunity-combining prior SARS-CoV-2 infection and vaccination-may offer enhanced protection, data on its effectiveness versus vaccine-induced immunity in the pediatric population are limited. <b>Methods</b>: This retrospective matched cohort study used linked health data from Norwegian nationwide health registries and the Italian Pedianet network. The study included children and adolescents aged 5-14 years eligible for COVID-19 vaccination at the time of approval (May/September 2021 and November 2021/January 2022, respectively). Mono- and two-dose vaccination schedules were assessed, and hybrid immunity was defined as prior SARS-CoV-2 infection followed by vaccination within 12 months. Conditional Cox regression models were used to estimate hazard ratios (HRs) for SARS-CoV-2 infection risk, adjusting for sociodemographics, comorbidities, and healthcare utilization. <b>Results</b>: The study included 626,537 children and adolescents in Norway and 38,938 in Italy. A single dose of the vaccine did not reduce the risk of infection among SARS-CoV-2-naive individuals in Norway (HR: 1.05; 95% CI: 1.04-1.07), whereas it was associated with an 8% risk reduction in Italy (HR: 0.92; 95% CI: 0.88-0.96). Among individuals with a recent prior infection (within 12 months), vaccination was associated with a reduced risk of reinfection in Norway (HR: 0.10; 95% CI: 0.05-0.13), but not in Italy (HR: 1.22; 95% CI: 0.83-1.80), compared to no vaccination. Among those with prior infection, vaccination was associated with a significantly reduced risk of reinfection in Norway (HR = 0.10; 95% CI: 0.05-0.20), but not in Italy (HR = 0.55; 95% CI: 0.27-1.11). Hybrid immunity provided greater protection against (re-)infection compared to vaccine-induced immunity alone, with a 26% risk reduction observed in Norway (HR = 0.74; 95% CI = 0.47-0.1.16) and an 86% reduction in Italy (HR = 0.14; 95% CI = 0.09-0.21). <b>Conclusions</b>: This analysis supports the effectiveness of SARS-CoV-2 vaccines in children, with hybrid immunity offering enhanced protection against reinfection. Given the waning effectiveness of vaccines over time, continued research and booster strategies are essential to sustain protection and mitigate transmission.