Protection of hybrid immunity against SARS-CoV-2 reinfection and severe COVID-19 during periods of Omicron variant predominance in Mexico

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.