The COVID-19 pandemic, initiated in December 2019, has been marked by the recurrent emergence of SARS-CoV-2 variants. Variants of concern (VOCs) such as Alpha, Beta, and Gamma emerged between October and December 2020, exhibiting increased transmissibility and/or immune evasion. The highly transmissible Delta variant subsequently displaced other VOCs globally. In late 2021, while a Delta wave subsided in southern Africa, a new variant, Omicron (B.1.1.529), was discovered almost simultaneously in South Africa and Botswana. Within weeks, it was identified in numerous countries and designated a VOC by the WHO. The study investigates the rapid spread of Omicron, focusing on its genomic characteristics and transmission dynamics in regions with high levels of pre-existing immunity.

Previous research established three distinct waves of SARS-CoV-2 infection in southern Africa, each driven by different variants: the first by descendants of the B.1 lineage; the second by the Beta VOC; and the third by the Delta VOC. Serosurveys indicated high SARS-CoV-2 exposure (40-60%) in South Africa before the Delta wave, rising to >70% in Gauteng by late 2021. Studies on prior VOCs, like Alpha, Beta, and Delta, highlighted their increased transmissibility and/or immune evasion capabilities, underscoring the need to understand Omicron's properties in the context of high population immunity.

The study employed genomic surveillance, PCR testing, and phylogenetic analysis. Omicron's detection began with an increase in COVID-19 cases and S-gene target failure (SGTF) in Gauteng, South Africa, which prompted targeted whole-genome sequencing. Concurrently, similar findings were reported in Botswana. The researchers collected and analyzed SARS-CoV-2 genomes from various locations in South Africa and Botswana. Phylogenetic analysis, including time-calibrated Bayesian phylogenetic analysis and spatiotemporal phylogeographic analysis, was used to infer the evolutionary origins, spread, and growth rate of Omicron. Molecular analysis characterized Omicron's mutations, focusing on spike protein mutations and their potential effects on antibody neutralization and transmissibility. Recombination analysis assessed whether Omicron resulted from recombination events, and selection analysis identified positively selected sites in Omicron's genome. Finally, modeling was used to estimate Omicron's growth advantage over Delta and investigate the roles of immune evasion and transmissibility.

Omicron's rapid spread was observed from mid-November 2021 in Gauteng, South Africa, with subsequent detection in other South African provinces and Botswana. Phylogenetics estimated Omicron's most recent common ancestor (TMRCA) around October 9, 2021, with a rapid doubling time (around 5 days). Spatiotemporal analysis indicated spread from Gauteng. Omicron carried numerous mutations, especially in the spike protein's receptor-binding domain (RBD), predicted to reduce neutralization by antibodies induced by previous infection or vaccination. Several mutations were near the S1/S2 furin cleavage site, potentially enhancing spike protein cleavage and fusion. Recombination analysis revealed weak evidence of recombination in the NTD-encoding region of the spike protein; however, the MRCA of BA.1, BA.2, and BA.3 lineages showed no evidence of recombination. Selection analysis found strong evidence of positive selection acting on multiple genes, particularly the spike protein, suggesting adaptive evolution. Omicron showed a substantial growth advantage over Delta in Gauteng, likely due to a combination of increased intrinsic transmissibility and immune evasion. Modeling suggested that immune evasion plays a significant role, even with high pre-existing immunity. By December 16, 2021, Omicron was detected in 87 countries.

The study's findings demonstrate Omicron's remarkable ability to evade immune responses acquired through previous infection or vaccination. Its rapid spread, even in regions with high population immunity, is likely driven by a combination of enhanced transmissibility and immune evasion. While neutralization assays revealed partial evasion of antibody responses, cellular immune responses are thought to be less affected by Omicron's mutations. This explains why vaccination remains a crucial preventative measure. The rapid spread of Omicron highlights the ongoing evolutionary pressure on SARS-CoV-2 and necessitates continued genomic surveillance and the development of new strategies to combat emerging variants.

The rapid detection and characterization of Omicron by robust genomic surveillance systems in southern Africa allowed for timely global alerts, enabling early response measures. Omicron's high transmissibility and significant immune evasion pose a considerable threat, particularly in regions with low vaccination rates. Continued monitoring is needed to fully understand its global dynamics and the effectiveness of existing countermeasures. Future research should focus on the long-term immune response to Omicron and the development of vaccines and therapeutics that can effectively address this and future SARS-CoV-2 variants.

Early sequence data may be biased due to targeted sequencing of SGTF samples and stochastic effects. Uncertainty exists regarding the precise levels of protective immunity in South Africa. The modeling's accuracy is contingent on the reliability of assumed immunity levels against Delta.