BACKGROUND: With widespread transmission of the Omicron SARS-CoV-2 variant, reinfections have become increasingly common. Here, we explored the role hybrid immunity, primary infection severity, and variant predominance on the risk of reinfection and severe COVID-19 during periods of Omicron predominance in Mexico. METHODS: We analyzed reinfections in Mexico in individuals with ≥90 days from a previous primary infection using a national surveillance registry of SARS-CoV-2 cases from March 3rd, 2020, until August 13th, 2022. Immunity-generating events included primary infection, partial or full vaccination and vaccine boosting. Reinfections were matched by age and sex with controls with primary SARS-CoV-2 infection and negative RT-PCR or antigen test ≥90 days after infection to explore risk factors for reinfection and reinfection-associated severe COVID-19. We also explored the protective role of heterologous vs. homologous vaccine boosters against reinfection or severe COVID-19 in fully vaccinated individuals. RESULTS: We detected 231,202 SARS-CoV-2 reinfections in Mexico, with most occurring in unvaccinated individuals (41.55%). Over 207,623 reinfections occurred during periods of Omicron (89.8%), BA.1 (36.74%) and BA.5 (33.67%) subvariant predominance and a case-fatality rate of 0.22%. Vaccination protected against reinfection, without significant influence of the order of immunity-generating events and provided >90% protection against severe reinfections. Heterologous booster schedules were associated with ~11% and ~54% lower risk for reinfection and reinfection-associated severe COVID-19 respectively, modified by time-elapsed since the last immunity-generating event. CONCLUSIONS: SARS-CoV-2 reinfections have increased during periods of Omicron predominance. Hybrid immunity provides protection against reinfection and reinfection-associated severe COVID-19, with potential benefit from heterologous booster schemes.

The authors have declared no competing interest.

FUNDING: This research was supported by Instituto Nacional de Geriatria.

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ETHICS APPROVAL: This project was registered and approved by the Ethics and Research Committee at Instituto Nacional de Geriatria, project number DI-PI-005/2021.

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DATA AVAILABILITY: All codes are available to assess statistical analysis at https://github.com/oyaxbell/reinfections_covid/. Data is available upon request to the General Directorate of Epidemiology of the Mexican Ministry of Health.

https://github.com/oyaxbell/reinfections_covid/