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The COVID-19 pandemic prompted rapid vaccine development and deployment worldwide. Despite widespread vaccination efforts, understanding the effectiveness of vaccines in hospitalized patients remains a critical concern. This retrospective cohort study, conducted at a tertiary healthcare centre in Serbia, tracked patients hospitalized during different waves of COVID-19 variants—Alpha, Delta, and Omicron. Data collection included demographics, comorbidities, symptoms, and vaccination status. Among 3593 patients, those with prior exposure to COVID-19 cases or hospital treatment showed higher positivity rates. Symptom prevalence varied across waves, with coughs persisting. Patients without chronic diseases were more frequent among those testing negative. Vaccine effectiveness varied, with Sinopharm demonstrating a 45.6% effectiveness initially and Pfizer-BioNTech showing an effectiveness of up to 74.8% within 0–84 days after the second dose. Mixed-dose strategies, notably Sinopharm as a primary dose followed by a Pfizer-BioNTech booster, suggested increased protection. Despite substantial vaccination availability, a significant portion of hospitalized patients remained unvaccinated. This study underscores the dynamic nature of vaccine effectiveness and advocates for booster strategies to address evolving challenges in combating COVID-19, particularly in hospitalized patients. [ABSTRACT FROM AUTHOR]