SARS-CoV-2 variant of concern (VoC), omicron, 2 was reported. Omicron emerged in a COVID-19-weary world in which anger and frustration with the pandemic are rife amid widespread negative impacts on social, mental, and economic wellbeing. Although previous VoCs emerged in a world in which natural immunity from COVID-19 infections was common, this fifth VoC has emerged at a time when vaccine immunity is increasing in the world. The emergence of the alpha, beta, and delta SARS-CoV-2 VoCs were associated with new waves of infections, sometimes across the entire world. 3 For example, the increased transmissibility of the delta VoC was associated with, among others, a higher viral load, 4 longer duration of infectiousness, 5 and high rates of reinfection, because of its ability to escape from natural immunity, 6 which resulted in the delta VoC rapidly becoming the globally dominant variant. The delta VoC continues to drive new waves of infection and remains the dominant VoC during the fourth wave in many countries. Concerns about lower vaccine efficacy because of new variants have changed our understanding of the COVID-19 endgame, disabusing the world of the notion that global vaccination is by itself adequate for controlling SARS-CoV-2 infection. Indeed, VoCs have highlighted the importance of vaccination in combination with existing public health prevention measures, such as masks, as a pathway to viral endemicity. 7

The first sequenced omicron case was reported from Botswana on Nov 11, 2021, and a few days later another sequenced case was reported from Hong Kong in a traveller from South Africa. 8 Several sequences from South Africa followed, after initial identification that the new variant was associated with an S-gene target failure on a specific PCR assay because of a 69–70del deletion, similar to that observed with the alpha variant. 9 The earliest known case of omicron in South Africa was a patient diagnosed with COVID-19 on Nov 9, 2021, although it is probable that there were unidentified cases in several countries across the world before then. In South Africa, the mean number of 280 COVID-19 cases per day in the week before the detection of omicron increased to 800 cases per day in the following week, partly attributed to increased surveillance. 10 COVID-19 cases are increasing rapidly in the Gauteng province of South Africa; the early doubling time in the fourth wave is higher than that of the previous three waves (figure, appendix). 10 The principal concerns about omicron include whether it is more infectious or severe than other VoCs and whether it can circumvent vaccine protection. Although immunological and clinical data are not yet available to provide definitive evidence, we can extrapolate from what is known about the mutations of omicron to provide preliminary indications on transmissibility, severity, and immune escape. Omicron has some deletions and more than 30 mutations, several of which (eg, 69–70del, T95I, G142D/143–145del, K417N, T478K, N501Y, N655Y, N679K, and P681H) overlap with those in the alpha, beta, gamma, or delta VoCs. 8 These deletions and mutations are known to lead to increased transmissibility, higher viral binding affinity, and higher antibody escape. 11, 12 Some of the other omicron mutations with known effects confer increased transmissibility and affect binding affinity. 11, 12 Importantly, the effects of most of the remaining omicron mutations are not known, resulting in a high level of uncertainty about how the full combination of deletions and mutations will affect viral behaviour and susceptibility to natural and vaccine-mediated immunity.