Background Since its emergence in November 2021 in southern Africa, the SARS-CoV-2 Omicron variant of concern (VOC) has rapidly spread across the world. There remain many unanswered questions about Omicron – in particular, in relation to its severity and the extent to which existing vaccines are effective in preventing COVID-19.Methods Using the Scotland-wide Early Pandemic Evaluation and Enhanced Surveillance of COVID19 (EAVE II) platform, which comprises of linked primary care, vaccination, reverse transcriptase polymerase chain reaction (RT-PCR), sequencing, hospitalisation and mortality data on 5.4 million (99% of the population), we undertook a cohort analysis with a nested test negative design incident casecontrol study covering the period November 1 to December 19, 2021 to provide initial estimates of Omicron severity and vaccine effectiveness (VE) against symptomatic disease. We used S gene status as a surrogate for Delta and Omicron VOCs, with S gene positive status indicating Delta whereas S gene negative indicated Omicron. Cox proportional hazard models were used to estimate the risk of COVID-19 hospitalisation adjusted for age, sex, socioeconomic status, vaccination status and clinical risk factors. Generalised additive logistic regression modelling with spline terms for age and sex were used to estimate VE relative to ≥25 weeks post second vaccine dose.Findings The first case of Omicron confirmed by viral sequencing was recorded in Scotland on November 23, 2021, By December 19, 2021, there were 23,840 S gene negative cases. These S gene negative cases were predominantly in the age group 20-39 (11,732; 49.2%). The proportion of S gene negative cases that were possible reinfections was more than 10 times that of S gene positive (7.6%versus 0.7%). There were 15 hospital admissions in those S gene negative giving an adjusted observed/expected ratio of 0.32 (95% CI 0.19, 0.52). The third/booster vaccine dose was associated with a 57% (95% CI 55, 60) reduction in the risk of symptomatic S gene negative symptomatic infection relative to ≥25 weeks post second dose.Interpretation These early national data suggest that Omicron is associated with a two-thirds reduction in the risk of COVID-19 hospitalisation when compared to Delta. Whilst offering the greatest protection against Delta, the third/booster dose of vaccination offers substantial additional protection against the risk of symptomatic COVID-19 for Omicron when compared to ≥25 weeks post second vaccine dose.