Abstract
INTRODUCTION: In December 2022, the zero - COVID strategy was amended, eliminating mandatory testing and isolation. The purpose of this study was to explore the effectiveness of targeted prevention measures in a key population (inmates and prison guards) and to provide data for similar situations in the future. METHODS: After the 2022 policy changes, a comprehensive 40 - day study was executed within the prison’s enclosed environment. 79,075 nucleic acid samples from facility entrants were collected, complemented by near-full-length viral genome sequencing using a targeted next-generation sequencing (tNGS) approach, to discern the impact of external non-pharmaceutical interventions (NPIs) on viral transmission within the institution. RESULTS: After two years without COVID − 19 cases, the prison’s streak ended abruptly due to changes in external NPIs. After two years without COVID-19 cases, the prison’s streak ended abruptly following the December 2022 policy shift. Continuous internal NPIs delayed the epidemic peak by ~ 5 days compared to the community. Critically, tNGS revealed nine distinct SARS-CoV-2 strains co-circulating on the first day of widespread testing among ordinary inmates (Dec 17, 2022)—providing direct genomic evidence of multiple external introductions. New variants continued to emerge over time. The 20× coverage decreased significantly in the later stage of the epidemic (p < 0.0001). The 20×coverage decreased significantly in the later stage of the epidemic (p < 0.0001). CONCLUSIONS: This study highlights that facility-specific NPIs—such as closed-loop management, quarantine for new admissions, and cohorting—can only delay, but not prevent, outbreaks driven by imported infections. It underscores the necessity for enhanced surveillance and expeditious testing in densely populated or confined quarters to identify and mitigate infection sources quickly. tNGS is an indispensable tool for validating superspreading events, deciphering transmission intricacies, and distinguishing strains among cases. CLINICAL TRIAL NUMBER: Not applicable. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12879-026-12725-9.