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

BACKGROUNDWith 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. METHODSWe 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. RESULTSWe 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. CONCLUSIONSSARS-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. RESEARCH IN CONTEXTO_ST_ABSEvidence before this studyC_ST_ABSWe searched PubMed for the terms "SARS-CoV-2" AND "reinfection" AND "hybrid immunity" until November 20th, 2022, and identified a few population studies previously conducted in Israel, Sweden, Qatar, United States and Canada which explored risk of reinfection and the protective role of hybrid immunity in individuals with one, two or three doses of COVID-19 vaccines, predominantly during periods of predominance of Omicron BA.1 and BA.2 subvariants. Notably, no studies were conducted in any Latin American country or reported on the benefit of heterologous booster schemes or the order of immunity-generating events. Added value of this studyWe report the results of nation-wide study in Mexico of over 230,000 SARS-CoV-2 reinfections, with [~]90% occurring during periods of Omicron predominance. We identified that vaccination provided additional benefit on reducing the risk of SARS-CoV-2 reinfection, with the highest benefit observed in individuals with complete vaccination and booster protocols prior to primary infection or with primary infection during periods of BA.1 and BA.2 subvariant predominance. Hybrid immunity also provides a substantial reduction in the risk of reinfection-associated severe COVID-19, with >90% reduction in risk compared to unvaccinated individuals with previous SARS-CoV-2 infection, regardless of the order of immunity-generating events. Finally, heterologous COVID-19 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. Implications of all the available evidenceOur results support that COVID-19 vaccination and boosters provide additional benefit to protect against SARS-CoV-2 reinfection and reinfection-associated severe COVID-19. The use of heterologous boosters appears to provide additional protection in previously infected individuals and such schemes may prove beneficial to increase vaccination coverage as newer, more transmissible variants emerge.