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

ABSTRACT Background Influenza 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. Methods We 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. Results Among 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). Conclusions Influenza 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.