Protection against Omicron re-infection conferred by prior heterologous SARS-CoV-2 infection, with and without mRNA vaccination

Importance Omicron is phylogenetically- and antigenically-distinct from earlier SARS-CoV-2 variants and the original vaccine strain. Protection conferred by prior SARS-CoV-2 infection against Omicron re-infection, and the added value of vaccination, require quantification. Objective To estimate protection against Omicron re-infection and hospitalization conferred by prior heterologous SARS-CoV-2 (non-Omicron) infection and/or up to three doses of (ancestral, Wuhan-like) mRNA vaccine. Design Test-negative study between December 26 (epi-week 52), 2021 and March 12 (epi-week 10), 2022. Setting Population-based, province of Quebec, Canada Participants Community-dwelling ≥12-year-olds tested for SARS-CoV-2. Exposures Prior laboratory-confirmed infection with/without mRNA vaccination. Outcomes Laboratory-confirmed SARS-CoV-2 re-infection and hospitalization, presumed Omicron by genomic surveillance. The odds of prior non-Omicron infection with/without vaccination were compared among Omicron cases/hospitalizations versus test-negative controls (single randomly-selected per individual). Adjusted odds ratios controlled for age, sex, testing-indication and epi-week. Analyses were stratified by severity and time since last non-Omicron infection or vaccine dose. Results Without vaccination, prior non-Omicron infection reduced the Omicron re-infection risk by 44% (95%CI:38-48), decreasing from 66% (95%CI:57-73) at 3-5 months to 35% (95%CI:21-47) at 9-11 months post-infection and <30% thereafter. The more severe the prior infection, the greater the risk reduction: 8% (95%CI:17-28), 43% (95%CI:37-49) and 68% (95%CI:51-80) for prior asymptomatic, symptomatic ambulatory or hospitalized infections. mRNA vaccine effectiveness against Omicron infection was consistently significantly higher among previously-infected vs. non-infected individuals at 65% (95%CI:63-67) vs. 20% (95%CI:16-24) for one-dose; 68% (95%CI:67-70) vs. 42% (95%CI:41-44) for two doses; and 83% (95%CI:81-84) vs. 73% (95%CI:72-73) for three doses. Infection-induced protection against Omicron hospitalization was 81% (95%CI: 66-89) increasing to 86% (95%CI:77-99) with one, 94% (95%CI:91-96) with two and 97%(95%CI:94-99) with three mRNA vaccine doses. Two-dose effectiveness against hospitalization among previously-infected individuals did not wane across 11 months and did not significantly differ from three-dose effectiveness despite longer follow-up (median 158 and 27 days, respectively). Conclusions and relevance Prior heterologous SARS-CoV-2 infection provided substantial and sustained protection against Omicron hospitalization, greatest among those also vaccinated. In the context of program goals to prevent severe outcomes and preserve healthcare system capacity, >2 doses of ancestral Wuhan-like vaccine may be of marginal incremental value to previously-infected individuals.