Study identifies two new Omicron lineages associated with a resurgence in infections in South Africa

In a recent study posted to the medRxiv* preprint server, researchers assessed the emergence and evolution of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Omicron variant in South Africa.

Study: Continued Emergence and Evolution of Omicron in South Africa: New BA.4 and BA.5 lineages. Image Credit: Viacheslav Lopatin/Shutterstock

By January 2022, the SARS-COV-2 Omicron BA.2 subvariant was reported to be the prevalent cause of coronavirus disease 2019 (COVID-19) infections in South Africa. However, the recent resurgence in SARS-CoV-2 cases, hospitalizations, and death was not associated with the BA.2 subvariant.

Study and results

In the present study, researchers identified two novel SARS-CoV-2 Omicron lineages designated BA.4 and BA.5.

Using the Bayesian phylogenetic methods, the team found that BA.4 and BA.5 were significantly different from the other Omicron lineages. The origin of BA.4 and BA.5 was estimated to be in December 2022 and January 2022, respectively. Phylogeographic analysis suggests that BA.4 dispersed from Limpopo to Gauteng with subsequent spread to other provinces, while BA.5 dispersed from Gauteng to KwaZulu-Natal to other provinces.

The team found that while BA.4 and BA.5 had similar spike proteins, these proteins were the most comparable to that of BA.2. Compared to BA.2, the BA.4 and BA.5 lineages had additional mutations on the spike protein. Other than the spike mutations, BA.4 had alterations at open reading frame (ORF)-7b:L11F and N:P151S along with a triple amino acid deletion in NSP1:141-143del, while BA.5 had the M:D3N mutation . Relative to BA.2, the BA.5 lineage also had additional reversions at nucleotide positions 26858 and 27259 as well as at ORF6:D61.

Additionally, BA.4 and BA.5 had nuc:G12160A mutation in non-structural protein (NSP)-8 that was also found in the SARS-CoV-2 epsilon (B.1.429) variant and was also observed in BA.2 at some locations. The team also found that the BA.4 and BA.5 lineages had mutational patterns identical to the 5′ genomic region in the SARS-CoV-2 envelope protein but displayed notable differences from the 3′ genomic region in the SARS-CoV-2 protein membrane. This indicated that BA.4 and BA.5 may be associated with each other via a recombinant event with a breakpoint between the membrane and the envelope genes.

The team remarked that the alterations in the spike amino acids at positions 452, 486, and 493 could influence antibody binding and human angiotensin-converting enzyme-2 (hACE2). The L452R mutation in the amino acid residue at 452 was associated with an improved affinity toward receptor binding, resulting in increased infectivity. This L452R mutation was also found in SARS-CoV-2 Delta, Kappa, and Epsilon variants. Furthermore, mutations at 452 were correlated with a decline in neutralization by monoclonal antibodies as well as polyclonal sera.

Selection analyzes that focused on the ratios of identical and nonsynonymous substitution rates at individual codons showed that S:486 was evolving under negative selection that favored the F state, that is, the amino acid present in the SARS-CoV-2 wild-type strain . When the spike amino acid F486 bound to hACE2, it interacted with the L79, M82, and Y83 residues found in hACE2. The team also found that the F486 mutations were associated with a decrease in the neutralizing activity by neutralizing antibodies and by polyclonal will be. Furthermore, mutational scanning indicated that F486 was a key site for the evasion of antibodies targeting the receptor-binding domain (RBD) induced by either vaccine or infection.

The team performed a quantitative polymerase chain reaction (qPCR) to examine the validity of S-gene target failure (SGTF) for identifying the BA.4 or BA.5 lineage in a sample. This was achieved by collecting 296 unselected samples between 6 January and 3 April 2022. Among the samples processed, 66 were either BA.4 or BA.5-infected, nine were BA.1-infected, while two were BA.2-infected . None of the BA.4 and BA.5 samples were positive for SGTF on qPCR, suggesting that SGTF could be employed to determine BA.4 and BA.5 samples only in regions with low BA.1 prevalence.

BA.4 and BA.5 were confirmed in seven South African provinces between 1 January 2022 and 20 April 2022. BA.4 was also identified in a smaller number of samples in the neighboring regions of Botswana, Europe, and the USA, while BA .5 was detected in some parts of Europe, the USA, and Hong Kong. The team estimated that BA.4 and BA.5 had a daily growth of 0.08 and 0.12, respectively.


Overall, the study findings showed that the researchers identified two novel SARS-CoV-2 Omicron sublineages, namely BA.4 and BA.5, which were responsible for the resurgence of COVID-19 infections in South Africa. The researchers believe that the study highlighted the need for continued global monitoring of emerging viral genomes to characterize the constant evolution of SARS-CoV-2.

*Important Notice

medRxiv publishes preliminary scientific reports that are not peer-reviewed and, therefore, should not be regarded as conclusive, guide clinical practice/health-related behavior, or treated as established information.


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