Dynamics of Influenza Vaccination and Respiratory Virus Infections in Children: A Multistate Model Approach

BackgroundInfluenza vaccination prevents influenza and influenza-like illness (ILI) in children, but its potential influence on susceptibility to other respiratory viruses remains unclear. We aimd to evaluate the relationships between influenza/ILI, non-influenza respiratory virus (NIRV) infections, and influenza vaccination in children. MethodsWe conducted a retrospective cohort study using real-world data from the Italian Pedianet pediatric network, including children aged 6 months to 14 years followed during two influenza seasons (September 2022-April 2023 and September 2023-April 2024). Multistate models were used to describe transitions over time between vaccination and infection states (influenza/ILI and NIRV), allowing events to occur in any order and enabling estimation of transition probabilities and timing. A Self-Controlled Case Series (SCCS) analysis using Poisson regression estimated the incidence rate ratio (IRR) of NIRV infection associated with vaccination, accounting for influenza/ILI and seasonality. ResultsAmong 91,695 children (median age 8 years; IQR 4-11; 51% male), vaccinated children showed delayed progression to NIRV infection and fewer early infections. Multistate models showed a substantially lower probability of transitioning to NIRV infection, by approximately 9- to >60-fold, in vaccinated vs unvaccinated children. In the SCCS analysis, influenza vaccination was associated with a reduced risk of NIRV infection (2022-2023:IRR 0.54; 95%CI,0.51-0.58; 2023-2024:IRR 0.60; 95%CI,0.56-0.64). ConclusionsInfluenza vaccination was associated with reduced NIRV infection risk in children, beyond its expected protection against influenza/ILI. These findings support virus interactions as a plausible mechanism shaping infection dynamics and reinforce the value of influenza vaccination in pediatric respiratory disease.