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.

The independent emergence late in 2020 of the B.1.1.7, B.1.351 and P.1 lineages of SARS-CoV-2 prompted renewed concerns about the evolutionary capacity of this virus to overcome public health interventions and rising population immunity. Here, by examining patterns of synonymous and non-synonymous mutations that have accumulated in SARS-CoV-2 genomes since the pandemic began, we find that the emergence of these three “501Y lineages” coincided with a major global shift in the selective forces acting on various SARS-CoV-2 genes. Following their emergence, the adaptive evolution of 501Y lineage viruses has involved repeated selectively favoured convergent mutations at 35 genome sites: mutations we refer to as the 501Y meta-signature. The ongoing convergence of viruses in many other lineages on this meta-signature suggests that it includes multiple mutation combinations capable of promoting the persistence of diverse SARS-CoV-2 lineages in the face of mounting host immune recognition.

A year of genomic surveillance reveals how the SARS-CoV-2 pandemic unfolded in Africa

South Africa’s fourth COVID-19 wave was driven predominantly by three lineages (BA.1, BA.2 and BA.3) of the SARS-CoV-2 Omicron variant of concern. We have now identified two new lineages, BA.4 and BA.5. The spike proteins of BA.4 and BA.5 are identical, and comparable to BA.2 except for the addition of 69-70del, L452R, F486V and the wild type amino acid at Q493. The 69-70 deletion in spike allows these lineages to be identified by the proxy marker of S-gene target failure with the TaqPath™ COVID-19 qPCR assay. BA.4 and BA.5 have rapidly replaced BA.2, reaching more than 50% of sequenced cases in South Africa from the first week of April 2022 onwards. Using a multinomial logistic regression model, we estimate growth advantages for BA.4 and BA.5 of 0.08 (95% CI: 0.07 - 0.09) and 0.12 (95% CI: 0.09 - 0.15) per day respectively over BA.2 in South Africa.

SARS-CoV-2 Omicron (B.1.1.529) BA.4 and BA.5 sub-lineages, first detected in South Africa, have changes relative to Omicron BA.1 including substitutions in the spike receptor binding domain. Here we isolated live BA.4 and BA.5 viruses and measured BA.4/BA.5 neutralization elicited by BA.1 infection either in the absence or presence of previous vaccination as well as from vaccination without BA.1 infection. In BA.1-infected unvaccinated individuals, neutralization relative to BA.1 declines 7.6-fold for BA.4 and 7.5-fold for BA.5. In vaccinated individuals with subsequent BA.1 infection, neutralization relative to BA.1 decreases 3.2-fold for BA.4 and 2.6-fold for BA.5. The fold-drop versus ancestral virus neutralization in this group is 4.0-fold for BA.1, 12.9-fold for BA.4, and 10.3-fold for BA.5. In contrast, BA.4/BA.5 escape is similar to BA.1 in the absence of BA.1 elicited immunity: fold-drop relative to ancestral virus neutralization is 19.8-fold for BA.1, 19.6-fold for BA.4, and 20.9-fold for BA.5. These results show considerable escape of BA.4/BA.5 from BA.1 elicited immunity which is moderated with vaccination and may indicate that BA.4/BA.5 may have the strongest selective advantage in evading neutralization relative to BA.1 in unvaccinated, BA.1 infected individuals.