Effect of Influenza Vaccination on the Disease Severity and Viral Load Among Adult Outpatients and Inpatients

<b>Background</b>: Some studies suggest that, thanks to the mechanisms of immune-mediated attenuation, influenza vaccination reduces severity of influenza illness in breakthrough infections. This study aimed to assess whether influenza vaccination attenuates severity of laboratory-confirmed influenza among Italian adults. <b>Methods</b>: This secondary analysis included all influenza cases detected during respiratory surveillance studies conducted in outpatient and inpatient settings in Genoa (Italy), throughout the 2023/2024 and 2024/2025 seasons. Here, we compared viral load and the count of influenza-related symptoms in outpatients, alongside all-cause in-hospital mortality and radiologically confirmed pneumonia in inpatients, between vaccinated and unvaccinated adults. <b>Results</b>: The study included 188 influenza cases diagnosed in primary care and 281 influenza cases identified among inpatients. Of these, 37.2% and 31.7%, respectively, were vaccinated, constituting breakthrough infections. Compared to unvaccinated adults, vaccinated outpatients had a slightly lower viral load (difference in cycle threshold values of 1.36 corresponding to about 0.51 log₁₀ reduction in the number of copies/mL; <i>p</i> = 0.077), primarily driven by influenza A(H1N1)pdm09. Vaccinated outpatients also reported 9% fewer influenza-related symptoms than unvaccinated counterparts [prevalence ratio 0.91; 95% confidence interval (CI): 0.84, 0.99]. Among hospitalized older adults, influenza vaccination was associated with 64% reduced odds of in-hospital death (odds ratio 0.36; 95% CI: 0.12, 0.94). Conversely, no association between vaccination and development of pneumonia was found. <b>Conclusions</b>: This study corroborates the idea that influenza vaccination attenuates disease severity in breakthrough infections. These effects are, however, dependent on the measure of severity used.