The story so far: In late November 2021, the World Health Organization designated the lineage B.1.1.529 of SARS-CoV-2 as a Variant of Concern (VoC) and assigned it the Greek alphabet Omicron. This variant was initially uncovered by researchers based on genomes from Southern Africa as well as travellers from the region and was characterised by a strikingly large number of mutations, particularly in its spike protein. The Omicron variant has now been detected in over 130 countries . The variant is now present in all seven continents and associated with an uptick of COVID-19 cases in the regions where it has been detected, including infections in fully vaccinated individuals or people who were previously infected with other variants of SARS-CoV-2. Omicron continues to dominate the pandemic in most regions since early 2022, although the massive surges seen in many countries have already peaked.
The timely detection and reporting of Omicron was a result of the efforts of researchers from South Africa, Botswana and Hong Kong who shared the initial genome sequences of the variant on GISAID, a database in which researchers from all over the world deposit sequencing data of SARS-CoV-2.
What are lineages?
The SARS-CoV-2 virus evolves by accumulation of genetic mutations. These form the basis of continued evolution of the virus and are produced during the process of infection and replication of the virus in the cells. Clusters of viruses with similar genomic mutations and a common origin are called a lineage or clade of the virus, and the naming of the lineages follow an open system contributed by researchers who form the PANGO network.
What are the sub-lineages of Omicron?
While the initial designation of the lineage was based on just 7 genomes, the designation of the lineage as a variant of concern by the WHO has seen an accelerated pace of screening and sequencing and as a consequence, a larger number of sequences representative of Omicron. As more genomes became available, researchers noted that not all sequences designated as Omicron had the full set of mutations that were initially reported for the variant. It was also observed that the Omicron cluster encompasses not just a single lineage but rather a family of three sister lineages branching from a common parent. These clusters were subsequently named as lineages BA.1, BA.2 and BA.3 (where BA is an alias for B.1.1.529). The VoC Omicron thus comprises all three sub-lineages, although each of them differs significantly from each other and contains common as well as unique mutations as compared to each other.
Of the clusters, BA.1 is the most prevalent Omicron lineage worldwide, accounting for over 97% of Omicron sequences. Lineage BA.2, although less prevalent globally, is becoming the most frequent variant in the recent weeks in many regions particularly in Europe and Asia. In Asia, BA.1 lineage is found in 85% of the total Omicron sequences while BA.2 makes up for 15% of them. The third sub-lineage, BA.3, is rare as of now, accounting for only a few hundred known cases globally and has not yet been reported from Asia.
What is the BA.2 lineage and how is it different?
As the number of COVID-19 cases is declining across many parts of the world, the lineage BA.2 is observed to be increasing in proportion in many countries and competing for dominance with the previously prevalent BA.1 lineage. Overall, the BA.2 lineage is now detected in over 50 countries.
While there are many mutations that BA.1 and BA.2 have in common, lineage BA.2 has 28 unique mutations as compared to BA.1 which makes it indicatively different from its sister lineage BA.1. This number is also higher than the number of defining mutations in any previously designated VoC, including Delta (lineage B.1.617.2) which is defined by a unique set of 17 mutations.
Databases which collect evidence on the functionality of mutations from published literature are key to understanding the functions of mutations as they become evident from genome sequences. One such database —ESC (https://clingen.igib.res.in/esc/) is maintained at the CSIR Institute of Genomics and Integrative Biology and systematically collects evidence for interpretation of genomes on immune escape mutations.
In terms of spike protein mutations, BA.2 has approximately 8 unique mutations as compared to BA.1, some of which are known to be associated with immune escape. However, BA.2 has been predicted to have lesser immune escape potential than BA.1, since it lacks the spike protein mutations R346K and G446S which are majorly associated with immune escape. Furthermore, mutations in the receptor-binding domain of the spike protein, the key part of the virus that allows it to latch on to the host’s cells, are largely shared by BA.1 and BA.2.
It is important to note that BA.1 has a mutation in the gene which encodes for the spike protein which causes one of the primers used in some RT-PCR diagnostic kits to fail (also known as the Spike Gene Target Failure (SGTF) or spike gene dropout). SGTF was used extensively across the world as a proxy for Omicron and enabled researchers to estimate the rapid spread of BA.1. However, BA.2 does not harbour this mutation in the spike protein and therefore does not cause a spike gene dropout. The prevalence today is therefore largely estimated through genome sequencing.
In contrast to spike protein mutations, there is a larger difference in mutations between BA.1 and BA.2 in the gene ORF1ab, with the lineage BA.2 harbouring 9 unique mutations as compared to BA.1 in the gene. ORF1ab gene codes for non-structural proteins in the virus that are responsible for controlling replication, proof-reading and inhibiting innate immunity of the host, possibly influencing transmissibility and disease severity.
Why is BA.2 being discussed?
The BA.2 lineage is seen to be increasing in many countries in Asia including India and Europe, which is an early indication that the lineage is more transmissible than its sister lineage BA.1.
Despite the decrease in COVID-19 cases in many regions in recent weeks, BA.2 has been seen to be competing with BA.1 and has become the prominent lineage in some countries including Denmark, where cases continue to rise. The BA.1 lineage was detected in Denmark in November 2021 while BA.2 was first detected a few weeks later in December. By the end of January 2022, BA.2 has outcompeted BA.1 in Denmark to become the dominant lineage in the country, and its prevalence is seen to be increasing in several other countries including India, the United Kingdom, Singapore, the Philippines and South Africa.
In India, BA.2 was first detected late in November 2021, 2 weeks after the detection of its sister lineage BA.1. BA.2 has since become the dominant Omicron lineage in India, increasing from 5% of all Omicron cases in December to over 50% by January 2022. In the United Kingdom, an increase in the number of cases linked to BA.2 has been seen since the first week of January 2022. In South Africa, where the Omicron variant was first detected, BA.2 is seen to be growing in prevalence in the recently sequenced samples, although the Omicron wave in South Africa continues to go down.
Is the BA.2 lineage more transmissible?
A preliminary risk assessment analysis by Statens Serum Institut in Denmark estimates that BA.2 is about 1.5 times more transmissible than BA.1. Another study conducted in Danish households and deposited in a preprint server before formal peer review, suggests that household transmission is higher among contacts of BA.2 infected individuals as compared to BA.1 indicating that BA.2 is intrinsically more transmissible than BA.1 . Whether this is driven by immune escape is still an open question. A preliminary combined report for all vaccines by the U.K. Health Security Agency shows that vaccine effectiveness against symptomatic COVID-19 was similar for BA.2 and BA.1 lineages, although the report is based on a small amount of data and further research will be required to perceive vaccine efficacy.
Since all early work done on Omicron was primarily focused on the BA.1 lineage, additional research will be needed to see how concerning the BA.2 lineage is. While there are increasing indications to show that BA.2 is more effectively transmitted than BA.1, there is limited evidence yet in terms of how different BA.2 is in terms of disease severity, very early data from countries like Denmark and India does not suggest a substantial difference in disease severity between BA.1 and BA.2.
What next?
As the SARS-CoV-2 continues to be transmitted and cause infections in a significant large number of people, it is apparent that it will continue to accumulate mutations at a heightened pace. Being the currently dominant lineage, it is expected that several more sub lineages of the Omicron variant are likely to come up in different regions of the world as the virus explores its evolutionary landscape and is similar to what was observed for Delta. In the context of the current Omicron wave, it is reassuring that vaccines and boosters continue to be effective in preventing severe disease. Whether BA.2 can cause reinfections in those previously infected with BA.1 and continue unabated is still an open question, for lack of evidence. Additional research efforts revolving around the BA.2 lineage in the upcoming weeks would help ascertain facts and address these pressing questions.
Meanwhile, in the periods of uncertainty, non-pharmacological interventions including good quality masks, ventilation and social distancing has become more important than ever in our fight against COVID-19.
The authors are researchers at the CSIR Institute of Genomics and Integrative Biology (CSIR-IGIB) in Delhi. All opinion expressed is personal.
