At our Pneumology Department, we dealt with three waves of COVID-19 pandemics. The purpose of this study is to compare patients' epidemiological and clinical characteristics across waves and to assess the effect of vaccination on clinical presentation, course, and prognosis. From March 2020 to March 2022, a retrospective cohort study was conducted to compare patient characteristics. Based on the time of hospital admission, data from 456 patients were collected and divided into three groups (IW, IIW, and IIIW). In addition, we looked at the link between vaccination and clinical presentation and hospitalization outcome. The average age and comorbidities of patients increased, as did the worsening of respiratory conditions at admission (PaO2/FiO2 median 207 in IW, 95.5 in IIW, and 99 in IIIW). Continuous positive airway pressure (CPAP) was the primary respiratory support during the first wave, but an increase in the use of high flow nasal cannula and noninvasive ventilation was later observed, resulting in a higher hospital discharge rate and a lower intubation rate. Vaccinated patients had less severe COVID-19-related respiratory failure, a better clinical course, and a higher hospital discharge rate (71.4% in V-group vs 44.7% in NV-group, p<0.001). Patients' characteristics changed over the three waves, possibly due to virus mutations. The advancement of clinical and therapeutic management knowledge has contributed to a reduction in the severity of respiratory failure. The vaccination campaign improved the clinical course and reduced mortality.