Background: Healthcare workers (HCWs) are particularly exposed to biological risk, including SARS-CoV-2 infection. In order to contrast the current pandemic and alleviate the burden of the disease on the healthcare system, a mass vaccination campaign against COVID-19 has been launched worldwide. Aim To evaluate the impact of COVID-19 vaccination in HCWs exposed to SARS-CoV-2, to describe the clinical presentation of COVID-19 in infected HCWs, and to investigate clinical and occupational risk factors for breakthrough infection. Design: Retrospective cohort study. Methods: The cohort of HCWs of Trieste Hospitals were followed up from 1 March 2020, to 30 November 2021 (21 months). All HCWs were periodically screened for SARS-CoV-2 infection by real-time PCR (RT-PCR) analysis. Clinical data were obtained through routine medical surveillance records. Risk factors for SARS-CoV-2 infection were investigated by univariable as well as multivariable logistic regression analysis. Results: Among 4394 HCWs routinely screened for SARS-CoV-2 by PCR on nasopharyngeal swab, a total of 800 incident cases were identified during the entire study period (1 March 2020 to 30 November 2021). Five hundred and sixty-four cases occurred before, and 236 after the start of the vaccination campaign against COVID-19, of whom 155 received a complete vaccination scheme before SARS-CoV-2 infection. Breakthrough infection was featured by mild or no symptoms and was significantly associated with the male sex, BMI > 25, and diabetes mellitus. Some categories of HCWs (physicians and nurse aids/auxiliary personnel) were at a higher risk of breakthrough infection. Conclusions: Fully vaccinated HCWs were less likely to acquire symptomatic as well as asymptomatic SARS-CoV-2 infection. Risk factors for SARS-CoV-2 infection after a full COVID-19 vaccination scheme included the male gender, diabetes mellitus, and overweight. HCWs with higher exposure to COVID-19 patients were at higher risk of breakthrough infection.

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