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To effectively curb coronavirus disease 2019 (COVID-19), it is essential to understand the risk factors for breakthrough acute infections of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) despite vaccination. We conducted a case-control study to assess risk factors for acute SARS-CoV-2 infections requiring hospitalization in vaccinated individuals. The study included 50 vaccinated patients who experienced breakthrough infections requiring hospitalization (inpatient cohort) and 250 control participants from the outpatient cohort of the "Genomic Surveillance and Immune Response Monitoring for COVID-19 in the Metropolitan Area of the Aburrá Valley, Medellín-Colombia". Demographic characteristics, vaccination status, and immune responses were compared between cases and controls using multivariate logistic regression. Advanced age (≥ 65 years), male sex, high-risk comorbidities, and immunosuppression were associated with an increased risk of breakthrough SARS-CoV-2 infections despite prior vaccination. In contrast, receipt of a booster dose and the presence of neutralizing antibodies were linked to a reduced risk of such infections. This study identifies key risk and protective factors associated with breakthrough SARS-CoV-2 infections. Derived from a high-middle-income setting, these real-world findings provide valuable insights to guide targeted vaccination strategies for vulnerable populations.