Emergence of SARS-CoV-2 Omicron lineages BA.4 and BA.5 in South Africa

Abstract

Three lineages (BA.1, BA.2 and BA.3) of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Omicron variant of concern predominantly drove South Africa's fourth Coronavirus Disease 2019 (COVID-19) wave. We have now identified two new lineages, BA.4 and BA.5, responsible for a fifth wave of infections. The spike proteins of BA.4 and BA.5 are identical, and similar to BA.2 except for the addition of 69-70 deletion (present in the Alpha variant and the BA.1 lineage), L452R (present in the Delta variant), F486V and the wild-type amino acid at Q493. The two lineages differ only outside of the spike region. The 69-70 deletion in spike allows these lineages to be identified by the proxy marker of S-gene target failure, on the background of variants not possessing this feature. BA.4 and BA.5 have rapidly replaced BA.2, reaching more than 50% of sequenced cases in South Africa by the first week of April 2022. Using a multinomial logistic regression model, we estimated growth advantages for BA.4 and BA.5 of 0.08 (95% confidence interval (CI): 0.08-0.09) and 0.10 (95% CI: 0.09-0.11) per day, respectively, over BA.2 in South Africa. The continued discovery of genetically diverse Omicron lineages points to the hypothesis that a discrete reservoir, such as human chronic infections and/or animal hosts, is potentially contributing to further evolution and dispersal of the virus.

Fig. 1. Molecular Evolution and Profile of BA.4 and BA.5 lineages.

a, Time-resolved maximum clade credibility phylogeny of the BA.2, BA.4 and BA.5 lineages (n = 221, sampled between 29 December 2021 and 7 April 2022). Mutations that characterize the lineages are indicated on the branch at which each first emerged. The posterior distribution of the TMRCA is also shown for BA.2, BA.4 and BA.5. b, Spatiotemporal reconstruction of the spread of the BA.4 lineage in South Africa. c, Spatiotemporal reconstruction of the spread of the BA.5 lineage in South Africa. In b and c, circles represent nodes of the maximum clade credibility phylogeny, colored according to their inferred time of occurrence (scale shown). EC, Eastern Cape; FS, Free State; GP, Gauteng; KZN, KwaZulu-Natal; LP, Limpopo; MP, Mpumalanga; NC, Northern Cape; NW, North West; WC, Western Cape. Solid curved lines denote the links between nodes, and the directionality of movement is indicated (anti-clockwise along the curve). d, Amino acid mutations in the spike gene of the BA.4 and BA.5 lineages. Mutations that differ from BA.2 are denoted in red, including the wild-type amino acid at position Q493 (denoted by the red asterisk (*)). NTD, N-terminal domain; SD1, subdomain 1; SD2, subdomain 2.

Fig. 2. Distribution of SARS-CoV-2 lineages in South Africa.

a, Changes in the genomic prevalence of Omicron lineages in South Africa from November 2021 (when BA.1 dominated) to May 2022 (when BA.4 and BA.5 were increasing in frequency), superimposed with the proportion of positive TaqPath qPCR tests exhibiting SGTF from November 2021 to May 2022. Estimations of genomic prevalence and SGTF proportions are done from different samples and datasets and presented together here only for illustrative purposes. b, The count of Omicron lineage genomes per province of South Africa over November 2021 to May 2022. BA.4 and BA.5 have been detected in all nine provinces. c, Modeled linear proportions of the Omicron lineages in South Africa. BA.1 rapidly outcompeted Delta in November 2021 and was then superseded by BA.2 in early 2022. BA.4 and BA.5 appear to be swiftly replacing BA.2 in South Africa. Model fits are based on a multinomial logistic regression, and dot size represents the weekly sample size. The shaded areas correspond to the 95% CIs of the model estimates. d, The progression of the 7-day rolling average of daily reported case numbers in South Africa over 2 years of the epidemic (April 2020 to May 2022). Daily cases are colored by the inferred proportion of SARS-CoV-2 variants prevalent at a particular period in the epidemic.

Extended Data Fig. 1. Molecular clock signal of the dataset of BA.2, BA.4 and BA.5 lineages used in the Bayesian analysis.

Root-to-tip regression obtained from TempEst analysis for the sampled cluster of BA.2, BA.4 and BA.5, showing a relatively strong clock-like behaviour (correlation coefficient = 0.6, R2 = 0.4) The regression line (representing the estimated mean evolutionary rate) is shown with error buffers (shaded area) that represent 90% confidence intervals.

Extended Data Fig. 2. Whole genome mutations present in BA.4 and BA.5 lineages.

Differences in BA.4 and BA.5 are highlighted with a rectangle. The synonymous mutations in nsp8 is indicated in red.

Extended Data Fig. 3. Patterns of natural selection between January 2020 and January 2022 at codon sites differentiating BA.4 and BA.5 from BA.2.

All SARS-CoV-2 sequences deposited in GISAID were analyzed with each time-point representing an analysis of all sequences sampled during the preceding three months. Red dots indicate evidence at positive selection and blue spots indicate evidence of negative selection. The sizes of the dots indicate degrees of statistical support for selection signals. Only sequences deposited in GISAID prior to the discovery of BA.4 and BA.5 are considered here.

Extended Data Fig. 4

Progression of the weekly genomic prevalence of various variants and lineages in the nine provinces of South Africa from November 2021 to May 2022.