Protective Effectiveness of Natural SARS-CoV-2 Infection and Vaccines against Omicron BA.4/BA.5 and XBB Reinfection in Singapore: A National Cohort Study

Background: Despite a large proportion of the population vaccinated and naturally infected, Singapore experienced SARS-CoV-2 waves driven by Omicron BA.5 and XBB sublineages. Data on the protective effectiveness of previous SARS-CoV-2 infections and vaccinations against Omicron BA.4/BA.5 and XBB reinfections remain scarce, and can be derived from Singapore’s experience as one of the first countries with an XBB-driven wave.Methods: Using official databases from the Singapore Ministry of Health, we conducted a retrospective cohort study among Singapore residents aged ≥18 years to assess hybrid immunity against BA.4/BA.5 reinfections from 1 October 2022 to 1 November 2022 and XBB reinfections from 18 October 2022 to 1 November 2022. Analysis stratified by time from first infection was also conducted to analyse waning immunity. Incidence rate ratios (IRR) were measured by Poisson regressions, with SARS-CoV-2-naive individuals as the reference group. Protective effectiveness (PE) was calculated by taking one minus the risk ratio.Findings: 2,456,791 individuals were included, contributing 53.1 million person-days of observation for the SARS-CoV-2-naive group, and 3.4, 6.6 and 13.7 million person-days to the groups with previous pre-Omicron, BA.1 and BA.2 infections respectively between 1 October 2022 and 1 November 2022. Compared with naïve individuals, first infections with pre-Omicron variants did not confer protection against BA.4/BA.5 (IRR 0.87 [95% CI 0.73–1.05] for pre-Omicron infection with booster) or XBB reinfection (IRR 1.29 [95% CI 1.23–1.35] for pre-Omicron infection with booster). Prior BA.2 infection with boosters provided the greatest protection, but this was lower against reinfection with XBB (PE 51%; 95% CI 49–53%) than BA.4/BA.5 (78%; 95% CI 74–82%). Protection by BA.2 against XBB reinfection also waned faster (74% [95% CI 72–75%) at 3–6 months to 49% [95% CI 47–52%] at 7–8 months) compared with BA.4/BA.5 reinfection (87% [95% CI 82–90%] at 3–6 months to 74% [95% CI 66–80%] at 7–8 months) over time from first infection.Interpretation: Protection from an earlier Omicron infection with vaccination against XBB reinfection was lower and waned faster than that for BA.4/BA.5 reinfection, indicative of XBB’s greater immune evasiveness. Populations remain vulnerable to future reinfection waves from emerging SARS-CoV-2 variants despite high rates of vaccination and natural infection, reflected by high reinfection rates during Singapore’s XBB wave.