Influenza Vaccine Effectiveness Against Mild and Severe Outcomes: A Comparison Study in Portugal.

BACKGROUND: Influenza vaccination is an effective public health intervention to lessen influenza effect on healthcare and has been recommended to prevent severe outcomes. Previous studies present higher influenza vaccine effectiveness (IVE) estimates against primary care medically attended (outpatients) compared to hospitalised cases (inpatients). Inconsistencies in study designs may hinder comparisons of IVE in preventing mild (outpatient consultations) versus severe influenza (inpatient admissions). We aimed to compare IVE against mild and severe influenza within primary care and hospital networks in Portugal from 2015/16 to 2023/24. METHODS: Using the test-negative design, we analysed 3393 RT-PCR-tested patients with influenza-like illness in outpatients or severe acute respiratory infection in inpatients. IVE was estimated using a generalised linear mixed model with fixed effects for sex, age category, comorbidities, month of symptom onset and random effects for season. For difference estimation, 95% confidence intervals (CI) were obtained through bootstrapping. RESULTS: IVE was 40.4% (22.7; 54.0) for outpatients and 38.7% (17.6; 54.5) for inpatients. The 1.7% difference was not statistically significant (-22.0; 26.8). Subgroup analyses for individuals aged ≥ 65 years, patients with comorbidities and by influenza A subtype showed similar non-significant differences, ranging from -1% to 17%. CONCLUSION: We found no statistically significant difference in IVE against mild or severe influenza infection. However, comparison across care settings should be interpreted cautiously, as patients differ in sociodemographic characteristics and comorbidity burden. Although limited sample size may reduce statistical power, the small magnitude of observed differences suggests that patients benefit from current vaccination strategies across care settings.