Abstract Since the emergence of Omicron variant of SARS-CoV-2 in late 2021, a number of sub-lineages have arisen and circulated internationally. Little is known about the relative severity of Omicron sub-lineages BA.2.75, BA.4.6, and BQ.1. We undertook a case–control analysis to determine the clinical severity of these lineages relative to BA.5, using whole genome sequenced, PCR-confirmed infections, between 1 August 2022 and 27 November 2022, among those who presented to emergency care in England 14 days after and up to one day prior to the positive specimen. A total of 10,375 episodes were included in the analysis; of which, 5,207 (50.2%) were admitted to the hospital or died. Multivariable conditional regression analyses found no evidence of greater odds of hospital admission or death among those with BA.2.75 (odds ratio (OR) = 0.96, 95% confidence interval (CI): 0.84–1.09) and BA.4.6 (OR = 1.02, 95% CI: 0.88– 1.17) or BQ.1 (OR = 1.03, 95% CI: 0.94–1.13) compared to BA.5. Future lineages may not follow the same trend and there remains a need for continued surveillance of COVID-19 variants and their clinical outcomes to inform the public health response.