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

## TL;DR

This study examines how SARS-CoV-2 breakthrough infections evolved in Yucatán, Mexico, during the Delta-to-Omicron transition, showing vaccines reduced severe outcomes and how relaxed travel rules increased Omicron spread.

## Contribution

The study provides real-world evidence of vaccine efficacy and links relaxed public health measures to increased Omicron introductions using combined epidemiological and genomic data.

## Key findings

- Vaccination reduced hospitalization and death risks in breakthrough infections compared to unvaccinated cases.
- Omicron infections were less severe than Delta but more transmissible, with diverse global origins.
- Relaxed travel restrictions correlated with increased Omicron introductions in Yucatán.

## Abstract

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 (n = 13,325) compared outcomes in BIs (n = 5,183) versus unvaccinated infections (UIs; n = 8,142) via logistic regression, also comparing Delta versus Omicron waves. Phylodynamic modeling of 205 BI sequences, contextualized globally (n = 1,152 total), reconstructed the evolutionary history and transmission routes. Vaccination significantly reduced hospitalization (odds ratio [OR] = 0.38) and death (OR = 0.45) in BIs compared to UIs. Omicron infections were less severe than Delta (hospitalization OR = 0.60; death OR = 0.33) and presented with less loss of smell/taste but more upper respiratory symptoms. Phylodynamics revealed numerous introductions (17 Delta, 36 Omicron). Delta BIs in Yucatán originated mainly from within Mexico, Guatemala, Europe, and the United States. Omicron BIs in Yucatán had more diverse origins including from North and South America and Africa, coinciding with eased travel restrictions. Vaccines maintained protection against severe outcomes during the Delta and Omicron waves in Yucatán. Omicron, though less severe, showed enhanced transmissibility with increased introductions linked to relaxed public health measures. Findings highlight the critical role of continued vaccination, genomic surveillance, adaptive policies, and cross-border collaboration for pandemic preparedness and health security.

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.