The introduction of variants of concern and interest in the Departamento of Antioquia, Colombia, was concomitant with the beginning of the COVID-19 immunization program. Genomic surveillance indicates that none of the emerging variants –alpha, gamma, lambda, mu or delta– were dominant between January and August 2021. The immunization includes CoronaVac, BNT162b2, Ad26.COV2.S and ChAdOx1-S vaccines. By September 10th, 34.43% inhabitants were fully vaccinated. We characterized, SARS-CoV-2 breakthrough infections in 96 patients, 30 with fatal outcomes, 13 with ICU hospitalization and 53 with mild or asymptomatic disease. Even though gamma and mu variants co-circulated at similar levels, the latter was found to be predominant in patients with fatal outcomes and in those with ICU hospitalizations. We found a significant occurrence of the B.1.625 variant in these patients. Genetic substitutions of therapeutic and immunological concern, E484K and N501Y, are consistently observed in 90.1% and 79.5% of these variants, respectively. Evidence suggests that it is less probable to become infected after 60 days post-treatment with BNT162b2 than with CoronaVac. Importantly, we found that advanced age and comorbidities foster conditions for fatal and ICU outcomes in vaccinated patients. Our observations demonstrate the effectiveness of vaccination and identify patients with higher risks of subsequent breakthrough infections.