Association between COVID-19 booster vaccination and influenza mortality: a nationwide retrospective cohort study using the SIVEP-Gripe database in Brazil.

To identify clinical and epidemiological predictors of mortality among patients hospitalized with laboratory-confirmed influenza in Brazil during 2024, and to evaluate the association of vaccination and antiviral therapy with clinical outcomes. We conducted a nationwide retrospective cohort study using the Brazilian SIVEP-Gripe surveillance database. All hospitalized patients with RT-PCR-confirmed influenza and known outcomes were included. Multivariable logistic regression was initially performed to explore predictors of mortality. To more rigorously assess the association between COVID-19 booster vaccination and mortality, a propensity score-based inverse probability of treatment weighting (IPTW) approach was applied, with weights truncated at 10. E-values were calculated to assess robustness to unmeasured confounding. A total of 15,995 hospitalized influenza cases were included, with an overall case fatality rate of 12.1%. Influenza A predominated (88.0%) and was associated with higher mortality than Influenza B. In IPTW-weighted models, COVID-19 booster vaccination remained independently associated with reduced mortality (OR 0.90, 95% CI 0.84-0.97; p = 0.007). Additional risk factors included dyspnea, respiratory distress, and low oxygen saturation, as well as comorbidities such as obesity, diabetes, liver disease, and immunosuppression. Protective factors included influenza vaccination (OR 0.77) and oseltamivir use (OR 0.81). The model demonstrated good discrimination (AUC = 0.81, 95% CI 0.80-0.82). The E-value for the booster association was 1.46, indicating moderate robustness to unmeasured confounding. Influenza mortality in Brazil is primarily driven by age, comorbidities, and clinical severity at presentation, but is significantly mitigated by vaccination and antiviral therapy. The observed association between COVID-19 booster vaccination and reduced mortality suggests a possible heterologous immune effect, although causality cannot be established. These findings support integrated immunization strategies targeting multiple respiratory pathogens.