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New SARS-CoV-2 may pose problems in controlling the COVID-19 pandemic for public health. We aimed to assess and compare the symptoms and severity of cases due to the Alpha and Delta variant dominance periods, taking into account the effect of COVID-19 vaccination. A prospective epidemiological study of SARS-CoV-2 in Lleida was made to determine differences between Alpha and Delta variants periods. We assessed symptoms, specific comorbidities, sociodemographic information and vaccination status. Bivariate and logistic regression analyses were used to estimate the adjusted odds ratio (aOR) and 95% confidence intervals (CI) to investigate the relationship between symptoms and severity and the variants. Alpha variant period compared to the Delta showed an increased risk of ICU admission (aOR 2.0; 95% CI 1.2–2.3) and death (aOR 2.6; 95% CI 1.8–3.9) and cases were associated with people …