Case-control and genomic epidemiology characterization of SARS-CoV-2 breakthrough infections during the Delta-to-Omicron transition.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccines reduced severe coronavirus disease 2019, but variants like Delta and Omicron caused widespread breakthrough infections (BIs). Mexico, offering diverse vaccines, and its Yucatán region, a major travel hub, provide a unique setting to study BIs. We characterized SARS-CoV-2 BIs in Yucatán during the Delta-to-Omicron transition (September 2021-January 2022), assessing disease severity, symptoms, and viral transmission dynamics using epidemiological and genomic data. A case-control study using health system data ( IMPORTANCE: Our understanding of severe acute respiratory syndrome coronavirus 2 breakthrough infections in Latin America is limited, specifically in regions with unique epidemiological dynamics. In this study, we fill a knowledge gap by characterizing these infections in Yucatán, Mexico, a major international travel hub with one of the world's most diverse vaccine rollouts, during the critical transition from the Delta variant to the Omicron variant. The translational importance of our investigation is twofold. First, through case-control data analysis, we provide robust, real-world evidence that vaccination significantly reduced the risk of hospitalization and death, offering crucial data to support ongoing vaccination campaigns against emerging variants. Second, by combining epidemiological data with phylodynamic analysis, we demonstrate a direct link between the easing of public health restrictions and the increased number and diversity of viral introductions that sparked the Omicron wave. This highlights the critical importance of coordinating genomic tracking with public health policy to mitigate the spread of future pandemic threats and strengthen global health security.