Effectiveness of bivalent mRNA vaccines against medically attended symptomatic SARS-CoV-2 infection and COVID-19-related hospital admission among SARS-CoV-2-naive and previously infected individuals: a retrospective cohort study

Background Emergence of the SARS-CoV-2 omicron (B.1.1.529) variant with high immune evasion has led to the development and roll-out of bivalent mRNA vaccines targeting original and omicron strains. However, real-world observational data on effectiveness of bivalent vaccines are scarce. We aimed to assess the relative effectiveness of a fourth vaccine dose with the BA.1-adapted or BA.4/BA.5-adapted bivalent vaccines against medically attended symptomatic SARS-CoV-2 infection and COVID-19-related hospital admission among SARS-CoV-2-naive and previously infected individuals in Singapore.Methods We conducted a retrospective cohort study among Singapore residents aged 18 years and older who had received three monovalent mRNA vaccine doses and were eligible for a fourth dose. Data were collected from official databases on COVID-19 cases and vaccinations maintained by the Singapore Ministry of Health. We analysed the incidence of medically attended symptomatic SARS-CoV-2 infection and COVID-19-related hospital admission between Oct 14, 2022, and Jan 31, 2023, by previous infection status and type of fourth vaccine dose received. Inverse probability-weighted Cox regressions were used to estimate hazard ratios (HRs). Findings 2 749 819 individuals were included in the analysis. For the SARS-CoV-2-naive group, a fourth monovalent vaccine dose did not confer additional protection over three monovalent doses against symptomatic infection (HR 1 center dot 09 [95% CI 1 center dot 07-1 center dot 11]), whereas the bivalent vaccine did provide additional protection (0 center dot 18 [0 center dot 17-0 center dot 19]). Among individuals with previous infection, the HR was 0 center dot 87 (95% CI 0 center dot 84-0 center dot 91) and 0 center dot 14 (0 center dot 13-0 center dot 15) with receipt of the fourth monovalent and bivalent doses, respectively. Against COVID-19-related hospital admission, the bivalent vaccine (HR 0 center dot 12 [95% CI 0 center dot 08-0 center dot 18] in SARS-CoV-2-naive participants and 0 center dot 04 [0 center dot 01-0 center dot 15] in previously infected participants) conferred greater benefit compared with the fourth monovalent dose (0 center dot 84 [0 center dot 77-0 center dot 91] in SARS-CoV-2-naive participants and 0 center dot 85 [0 center dot 69-1 center dot 04] in previously infected participants). Interpretation A fourth dose with the bivalent vaccine was substantially more effective against medically attended symptomatic SARS-CoV-2 infection and COVID-19-related hospital admission than four monovalent doses among both SARS-CoV-2-naive and previously infected individuals. Boosters with the bivalent vaccine might be preferred in this omicron-predominant pandemic, regardless of previous infection history.