Tehran University of Medical Sciences Iranian Journal of Microbiology 2008-3289 17 2 2025 04 05 194 203 Vanathy Kandhasamy Department of Microbiology, Mahatma Gandhi Medical College & Research Institute (MGMCRI), Sri Balaji Vidyapeeth (Deemed to be University), Pondicherry, Puducherry, India Ramya Priyadarshini Department of Microbiology, Mahatma Gandhi Medical College & Research Institute (MGMCRI), Sri Balaji Vidyapeeth (Deemed to be University), Pondicherry, Puducherry, India Namrata Bhosale Department of Microbiology, Vinayaka Mission's Medical College and Hospital, Vinayaka Mission’s Research Foundation (Deemed to be University), Karaikal, Puducherry, India Raji Pillai Department of Microbiology, Mahatma Gandhi Medical College & Research Institute (MGMCRI), Sri Balaji Vidyapeeth (Deemed to be University), Pondicherry, Puducherry, India Malarvizhi Ramalingam Department of Microbiology, Mahatma Gandhi Medical College & Research Institute (MGMCRI), Sri Balaji Vidyapeeth (Deemed to be University), Pondicherry, Puducherry, India Agiesh Balakrishna Pillai Department of Virology, Scientist F, Advanced Institute of Virology, Trivandrum, Kerala, India Ezhumalai Govindasamy Department of Deanery Research, Sri Balaji Vidyapeeth (Deemed to be University), Pondicherry, Puducherry, India Joshy Maducolil Easow Department of Microbiology, Mahatma Gandhi Medical College & Research Institute (MGMCRI), Sri Balaji Vidyapeeth (Deemed to be University), Pondicherry, Puducherry, India 2024 12 14 2025 03 08 Background and Objectives: The COVID-19 pandemic was mitigated by the rapid development and deployment of vaccines. While vaccines reduce infection severity, breakthrough infections (BTIs) still occur. The CDC defines BTI as a positive SARS-CoV-2 test ≥14 days post-vaccination. This study investigates the occurrence of COVID-19 BTIs at a tertiary care hospital in Puducherry, South India. Materials and Methods: This retrospective study analysed hospital tested qRT-PCR data of individuals from the ICMR portal (March 2021–March 2022). Demographic and vaccination details were extracted. Results: Among 8001 tested individuals, 1452 were vaccinated. The BTI rate decreased from 16.6% to 1.2% after the first dose and from 58% to 40% after the second one. Odds ratio indicated a 74% reduction in infection risk for vaccinated individuals compared to unvaccinated. Males had higher infection rates than females, regardless of vaccination status. Conclusion: Our study demonstrates a higher BTI rate after one vaccine dose compared to two doses. The BTI rate also increased four months post-vaccination, even with two doses, potentially due to waning immunity and the emergence of new variants. Therefore, continued adherence to preventive measures in conjunction with vaccination is crucial for minimizing COVID-19 transmission. https://ijm.tums.ac.ir/index.php/ijm/article/view/5200 https://ijm.tums.ac.ir/index.php/ijm/article/download/5200/1757