BackgroundThe Belgian COVID-19 vaccination campaign aimed to reduce disease spread and severity.AimWe estimated SARS-CoV-2 variant-specific vaccine effectiveness against symptomatic infection (VEi) and hospitalisation (VEh), given time since vaccination and prior infection.MethodsNationwide healthcare records from July 2021 to May 2022 on testing and vaccination were combined with a clinical hospital survey. We used a test-negative design and proportional hazard regression to estimate VEi and VEh, controlling for prior infection, time since vaccination, age, sex, residence and calendar week of sampling.ResultsWe included 1,932,546 symptomatic individuals, of whom 734,115 tested positive. VEi against Delta waned from an initial estimate of 80% (95% confidence interval (CI): 80–81) to 55% (95% CI: 54–55) 100–150 days after the primary vaccination course. Booster vaccination increased initial VEi to 85% (95% CI: 84–85). Against Omicron, an initial VEi of 33% (95% CI: 30–36) waned to 17% (95% CI: 15–18), while booster vaccination increased VEi to 50% (95% CI: 49–50), which waned to 20% (95% CI: 19–21) 100–150 days after vaccination. Initial VEh for booster vaccination decreased from 96% (95% CI: 95–96) against Delta to 87% (95% CI: 86–89) against Omicron. VEh against Omicron waned to 73% (95% CI: 71–75) 100–150 days after booster vaccination. While recent prior infections conferred higher protection, infections occurring before 2021 remained associated with significant risk reduction against symptomatic infection. Vaccination and prior infection outperformed vaccination or prior infection only.ConclusionWe report waning and a significant decrease in VEi and VEh from Delta to Omicron-dominant periods. Booster vaccination and prior infection attenuated these effects.