Background: Evidence suggests that vaccines efficacy lies on the prevention of severe symptomatic disease. We aim to describe the clinical characteristics of COVID-19 infection among healthcare professionals (HCPs) after vaccination, during periods of transmission of SARS CoV-2 variants in a COVID-19 dedicated facility. Methods: A retrospective observational study of HCPs confirmed with COVID-19 during the period March 2021 to Jan 2022 was conducted. Delta period (March-August 2021), and Omicron period (Dec 2021- Jan 2022) were defined. Clinical, laboratory, radiology and vaccination history was collected from electronic medical records. Results: COVID-19 infection was reported in 16 and 138 HCPs during the Delta and Omicron period respectively.By category the nurses predominate, and a significant contribution of the healthcare related transmission against the community-related one. Higher frequency of loss of taste (37.5% vs 4.3%), and loss of smell (43.8% vs 3.6%) was observed during Delta period. Myalgia (12.5% vs 37.7%), and sore throat (6.3% vs 55.8%) predominated in Omicron period. Bilateral ground-glass appearance of the lung was observed in 28.6% and 7.1% in the Delta and Omicron period, respectively. Higher cycle threshold values of the polymerase chain reaction test during Omicron period, in comparison with Delta period, was observed (22.98 vs 25.98). Time from previous vaccine dose to positive laboratory test was longer during the Delta period (131 vs 98.26 days). Conclusion: SARS CoV-2 viral variants infections in HCPs were associated to selected clinical and epidemiological characteristics, with less severe disease for Omicron variant, and potential shorter duration of the immune response to vaccination.