We analysed the impact of Alpha, Delta and Omicron SARS-CoV-2 lineages throughout the three sequential waves of these variants in the UK. In summary, the cumulative vaccination rate increased by over 12-fold throughout the study period, while the odds of coronavirus disease 2019 (COVID-19) related hospitalizations declined by 78% and 83% from Alpha to Delta and Alpha to Omicron periods. Likewise, COVID-19 related deaths declined by 93% and 95% from Alpha to Delta and Alpha to Omicron periods. Widespread vaccination and SARS-CoV-2 mutation seem thus to have combined to modify the scenario, with early signs of endemicity.