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Objective A cohort study was conducted with the support of the WHO, where a standardized WHO protocol was followed to assess vaccine effectiveness (VE) against symptomatic RT‒PCR confirmed SARS‒CoV-2 infection among hospital health workers (HWs) eligible for vaccination at Al-Azhar University hospitals. Methods A WHO-supported cohort study was conducted from July 2022 through September 2023 and included 1249 HWs who were randomly selected and followed up biweekly for one year. At enrollment, nasopharyngeal (NP) and blood samples were collected from each participant and evaluated to detect SARS-CoV-2 RNA via a real-time PCR assay (QIAGEN) and for the quantitative detection of SARS-CoV-2 binding antibodies via the Roche Elecsys Anti-SARS-CoV-2 S immunoassay (Roche Diagnostics, GmbH, Germany). During follow-up, NP samples were collected from anyone who developed symptoms consistent with the WHO definition of suspected cases of SARS-CoV-2 infection. Results At enrollment, SARS-CoV-2 RNA was detected in 119/1235 (9.6%) HWs and 89% of the participants with positive RNA were asymptomatic. COVID-19-binding antibodies were detected among 1245/1248 (99.8%) HWs, and 53.2% of them had titers > 2500 U/mL, regardless of vaccination status. During follow-up, 232 participants had COVID-19 symptoms, but only 108 provided NP samples, and 18 (16.7%) of them were positive for SARS-CoV-2 RNA. No hospitalization or mortality was recordedat enrollment or during the follow-up period. The cumulative incidence of COVID-19 infection was higher among HWs with incomplete vaccination compared to unvaccinated, fully vaccinated, or those who received booster doses ( P  = 0.025). There was no significant difference in VE among HWs who were fully vaccinated or had booster doses compared with unvaccinated HWs, with adjusted VE values of 68% (95% CI -28–92%) and 64% (95% CI -170–95%), respectively ( P  = 0.106 and 0.318 respectively). The adjusted VE increased to 89% (95% CI -33–99%) among HWs with hybrid immunity compared with those who were unvaccinated with a previous COVID-19 infection ( P  = 0.082). Conclusion This study indicates that VE against symptomatic lab-confirmed SARS-CoV-2 infection was quite high with over 60% protection and was higher among HWs with hybrid immunity (immunity due to a combination of previous infection and vaccination) compared to unvaccinated HWs with previous COVID-19 infection. The findings also highlight the importance of completing the primary vaccination series against COVID-19. This study reveals a high rate of asymptomatic COVID-19, a lower rate of confirmed cases, who showed marked decrease in hospitalization and fatality rates. Real-world VE studies are essential to address several unresolved issues, such as the appropriate number of booster doses and the longevity of protection.