Late in November 2021, World Health Organization (WHO) designated the B.1.1.529 lineage of SARS-CoV-2 as Variant of Concern (VOC) Omicron. The swift rise of Omicron and displacement of previous lineages of SARS-CoV-2 across the world, particularly Delta, was suggestive that Omicron not only had a fitness advantage over Delta but also had the ability to infect people who had prior immunity to Delta or any previous lineages of the virus.
Three sister lineages
During its designation in 2021, VOC Omicron initially comprised three sister lineages: BA.1, BA.2 and BA.3, although each lineage differs significantly from the other in terms of its mutations. While lineage BA.3 remained relatively rare, lineages BA.1 and BA.2 were primarily responsible for the upsurge in COVID-19 cases across different countries, and also causing infections in fully vaccinated individuals — otherwise known as vaccine breakthrough infections. Over the time, BA.2 became the predominant Omicron lineage worldwide.
As of today, over 100 sub lineages of Omicron have been detected and designated from different regions of the world.
In April 2022, genome sequencing efforts by researchers in South Africa helped identify two new Omicron lineages in the region, which have been later designated by the Phylogenetic Assignment of Named Global Outbreak (PANGO) network as BA.4 and BA.5. The detection of the two lineages also coincides with an upswing in the numbers of COVID-19 cases seen in South Africa, briefly after a decline in numbers since the previous Omicron wave.
The two lineages have been driving the new wave of cases in South Africa, now touching over 10,000 cases daily and a test positivity of over 26%. Further, researchers in South Africa suggest that the two lineages BA.4 and BA.5 can escape immunity acquired through BA.1 infection.
Although not yet detected in India, the BA.4 and BA.5 lineages have been detected in low numbers in over 15 other countries, including the United Kingdom, Austria, Germany and the USA.
Early studies from South Africa estimate that BA.4 and BA.5 have a significant growth advantage over the BA.1 as well as BA.2 lineage, which could either be because of an ability of the lineages to transmit better or an ability to escape immunity from previous infections or vaccination. While significantly different from the original BA.1 lineage, BA.4 and BA.5 have an identical spike protein. Compared to BA.2, both BA.4 and BA.5 differ from the dominant Omicron lineage by three mutations and one deletion. One of the three distinct mutations found in the BA.4 and BA.5 lineages is L452R in the spike protein of the virus.
L452R mutation
Mutations at position L452R was found in Delta along with Kappa and Epsilon, while variant Lambda had L452Q. These mutations have been previously reported to be associated with increased infectivity of the virus and also has the ability to evade neutralisation by monoclonal antibodies. Preliminary research shows that BA.4 and BA.5 lineages may be capable of escaping immunity gained by a previous BA.1 infection. Preliminary evidence emerging in a preprint from South Africa also suggests that vaccines are potentially better in protecting against infection as compared to previous infection with BA.1. More evidence is required to understand the clinical outcomes of the new lineages.
The L452 mutations in the spike protein are not unique to BA.4 and BA.5 Omicron lineages but have also emerged independently in other Omicron sublineages in different countries. This includes the mutation L452Q in lineage BA.2.12.1, a sublineage of BA.2, which is recently seen to dominate COVID-19 cases in New York. As the number of infections continues to surge in the USA, proportions of BA.2.12.1 have also been seen to slowly increase, although the cases in the country continue to be dominated by its parent lineage BA.2.
As the Omicron variant continues to dominate the pandemic across the world, it is expected that additional sub-lineages of the variant will emerge as the virus continues to accumulate mutations. As the wave of infections progress, in South Africa and elsewhere more granular data is expected in the coming weeks which would throw light into whether these lineages, including BA.4 and BA.5, are capable of causing waves of infections in different countries or if they are able to prolong the ongoing surges by replacing the currently dominant BA.2 lineage.
Current evidence is insufficient to ascertain what will be the impact of these new variants on vaccine efficacy and other clinical outcomes compared to previous variants. Enhanced genome sequencing efforts, rapid sharing of genomic and epidemiological data also remain essential for detecting and tracking the prevalence of Omicron lineages. Irrespective of emerging variants, controlling transmission of the virus through non-pharmacological interventions like masking and increasing ventilation should remain the priority, apart from protecting the vulnerable through precautionary doses of vaccines.
( Bani Jolly and Vinod Scaria are researchers at the CSIR Institute of Genomics and Integrative Biology (CSIR-IGIB) in Delhi)
