Effectiveness of the quadrivalent live attenuated influenza vaccine against influenza-related hospitalisations and morbidity among children aged 2 to 6 years in Denmark: a nationwide cohort study emulating a target trial

Background Scant evidence exists on the real-world effectiveness of quadrivalent live attenuated influenza vaccines (LAIV-4) in younger children. We aimed to assess the real-world effectiveness of LAIV-4 against influenza-related hospital contacts and admission and morbidity. Methods Using nationwide Danish health-care registries, we designed a cohort study that emulates a target trial, comparing LAIV-4 to no vaccination in children aged 2–6 years. Eligible children vaccinated from Oct 1, 2021, to Jan 15, 2022, were matched to unvaccinated controls in a 1:1 ratio according to demographic characteristics and risk groups for influenza, and followed-up until May 31, 2022. Primary study outcomes any hospital contact for influenza and influenza-related hospital admissions more than 12 h in duration, while hospital admission for respiratory tract infections, or for wheezing or asthma, and antibiotic prescriptions were evaluated as secondary outcomes. We estimated incidence rate ratios (IRRs) and 95% CIs using Poisson regression for each outcome. Vaccine effectiveness was calculated as 1 – IRR. Findings Among 308 520 Danish children aged 2–6 years, 95 434 vaccinated children were matched with 95 434 unvaccinated children who acted as controls. Receipt of LAIV-4 compared with no vaccination was associated with a reduced IRR of 0·36 (95% CI 0·27 to 0·46) and estimated vaccine effectiveness of 64·3% (53·6 to 72·6) against influenza-related hospital contacts (76 vs 210 events). The corresponding IRR and vaccine effectiveness against influenza-related hospital admissions were 0·63 (0·38 to 1·05) and 36·9% (–5·2 to 62·1; 24 vs 38 events), respectively. LAIV-4 was not associated with reductions in admission rates for respiratory tract infections (IRR 1·14, 95% CI 0·94 to 1·38), wheezing or asthma (1·04, 0·83 to 1·31), or antibiotic prescriptions for respiratory tract infections (0·97, 0·93 to 1·00). Vaccine effectiveness assessed across risk groups for influenza showed similar effectiveness in children with and without coexisting risk factors for severe influenza. Interpretation LAIV-4 offered moderate protection in younger children against influenza-related hospital contacts during a season dominated by influenza A(H3N2); however vaccination was not associated with reductions in secondary outcomes. This real-world study thereby supports trial evidence of moderate vaccine effectiveness of LAIV-4 against influenza-related outcomes when implementing broad vaccination schedules in younger children. Funding Beckett-Fonden