The new Omicron sub-lineage may not further increase transmissibility

Developments pertaining to the new variant Omicron (B.1.1.529) are happening thick and fast. Days after the WHO designated Omicron as a variant of concern, the variant has been split into two sub-lineages — BA.1, “for the original globally-distributed lineage”, and BA.2, “for the new outlier lineage”. The sub-lineages BA.1 and BA.2 are two divergent clusters with a common ancestor.

The World Health Organization designated Omicron as a variant of concern on November 26, three days after the genome sequence was deposited in a public database by South Africa and Botswana.

Now, based on genome sequence data, scientists have identified a sub-lineage — BA.2 — of Omicron. As a result, the Omicron variant has been split into two sub-lineages, namely BA.1, “for the original globally-distributed lineage”, and BA.2, “for the new outlier lineage”. 

Why is BA.2 called a sub-lineage?

The BA.2 has a “cluster of sequences that share many of the same mutations as the ‘original’ Omicron (BA.1) but is missing some mutations and has some other new ones,” Dr Emma Hodcroft, co-developer of Next Strain tweeted. The new sub-lineage of Omicron has been designated BA.2, and the initially seen lineage has been designated as sub-lineage BA.1. The BA is an alias for B.1.1.529, now redefined to encompass both BA.1 and BA.2.

While BA.2 is genetically quite different from the sub-lineage BA.1, BA.1 and BA.2 are two divergent clusters with a common ancestor, says a senior scientist. Both BA.1 and BA.2 are equal sub-lineages of B.1.1.529.

Since BA.1 and BA.2 have a common ancestor, how many mutations in the spike protein are common to both BA.2 and BA.1 and how many are unique to each sub-lineage?

The B.1.1.529 cluster, which includes both BA.1 and BA.2, has 85 mutations in all, of which, 40 mutations are in the spike protein alone. While 12 mutations have been found exclusively in the spike protein of BA.1, the BA.2 sub-lineage has seven exclusive mutations in the spike protein. Twenty-one mutations in the spike protein are common to both BA.1 and BA.2

How many BA.2 samples have been sequenced so far?

As on December 9, the genome sequence data from seven samples across the world have been posted on the public database. Of the seven, five sequences have been deposited from Canada, and one each by South Africa and Australia.

The genome sequence was deposited by South Africa on November 27, while Canada and Australia deposited their sequences on December 6.

Compared to the small number of BA.2 genome sequences deposited so far, there are over 1,000 sequences of BA.1 that have been deposited in the database from across the world.

Can it be said that the sub-lineage BA.2 is of recent origin?

No, it cannot be said that the sub-lineage is of recent origin. The reason: only seven samples have been genome sequenced and this makes it difficult to accurately estimate the time of origin of the sub-lineage BA.2

Can the sub-lineage BA.2 be identified by RT-PCR tests?

Yes, the new sub-lineage identified recently cannot be identified by the primers used in the RT-PCR test. While the BA.1 sub-lineage carries the characteristic S-gene dropout mutation, the BA.2 does not have this mutation.

The currently used primers in RT-PCR tests carry sequences that target three genes, one of which is the S-gene. Since the BA.1 sub-lineage carries the S-gene dropout mutation, only two of the three targets in the primer will turn positive when the BA.1 sample is tested by RT-PCR. The S-gene in the primer does not test positive due to the presence of the S-gene dropout mutation. The test being positive for two genes but not for the S-gene is a convenient way of knowing that the sample tested is a sub-lineage BA.1 of the Omicron variant. In short, the S-gene dropout is a proxy to identify the BA.1 sub-lineage.

Since BA.2 does not carry the S-gene dropout mutation, all the three target sequences in the RT-PCR primer will test positive. Hence it will not be possible to straightaway know if the sample tested is a sub-lineage of the Omicron variant. Only by genome sequencing can one identify if a sample belongs to the BA.2 sub-lineage.  

Will the BA.2 sub-lineage have far higher transmissibility and/or immune escape than the BA.1 sub-lineage?

According to a senior scientist, the additional seven mutations in the spike protein do not provide sufficient evidence in terms of increased immune escape and transmissibility. Even individually, these seven mutations have not been implicated with either significant immune escape or enhanced transmission. As of now, the combined effect of the seven mutations is not known either.

“The designation aims to aid scientific discussion and does not imply an assessment of the lineages’ transmission properties,” the Pango Network said in a tweet.

Do the two sub-lineages change the manner in which patients are clinically managed?

No, the clinical management of patients with any degree of disease severity remains the same immaterial of whether they have been infected with one of the Omicron sub-lineages or the Delta variant.

Published in The Hindu on December 12, 2021