How Concerned Should You Be About AY.4.2. Delta Subvariant? An Expert Explains

Just when you thought that all the talk about new COVID variants was over there is news of another: AY.4.2. What is it? Where did it come from and should it be of concern to us?
A "lineage" is what AY.4.2 stands for. These labels are given to COVID branches to show their relationship. The Pango network, an international team of researchers from Oxford and Edinburgh, oversees them and assigns new lineages.

We can trace the origins and development of AY.4.2 back to April this year. As part of Cog-UK, a British consortium that sequences COVID genomes to determine how the virus is evolving, our team in Northumbria had just sequenced two travel history samples from India.

We knew at the time that the Indian lineage was B.1.617. However, the cases we sampled did not match this. Variants can be distinguished by the various mutations they have in genetic material. Looking at our samples, we saw that our cases did not contain some of the B.1.617 mutations, but had several others.

The information we reported to Cog-UK colleagues was classified as B.1.617.2, which is one of the three main sub-lineages that make up B.1.617.2. It was later renamed delta by the World Health Organization.

The next evolutionary step is AY. A new combination of letters is used to prevent a lineage's name from getting too long once it has reached five levels in its labelling. The AY forms of this virus don't differ from the ones that came before them, even though they have different labelling. All are sub-lineages within the delta.

There are 75 AY lineages, each with a different set of defining mutations. One of these AY.4 lines has been steadily increasing in UK in recent months. It accounts for 63 percent new UK cases within the past 28 days.

Is AY.4 an advantage?

We are still not certain if AY.4's mutations confer a real advantage or if increasing frequencies of the lineage is just down to what's known as a "founder effect". This occurs when a subset or group of viruses is separated from the entire viral population and reproduces in isolation. All subsequent viruses will be descendants of the subset that was separated.

This could have been possible with COVID if there was only one case at large events. The "founder" would have been the virus that spread at the event. It could have infected many people and then infected others. This could have led to a lot of viruses from the same source. Sometimes, a particular virus form doesn't need to be superior to others to become dominant. It just needs to be at the right place at right time.

AY.4 may have a distinct advantage due to its dominance in the UK. The mutation A1711V is the most significant change in AY.4. It affects Nsp3 protein which plays a variety of roles in viral replication. The impact of this mutation remains to be determined.

This is AY.4.2, a sub-lineage from AY.4, which was first discovered at the end September. However, it seems it appeared in the UK sometime around June. Two additional genetic mutations affect the spike protein, Y145H, and A222V. The virus's spike protein, which is an important part of its outer surface, is what it uses to enter cells.

AY.4.2's volume has steadily increased to the point that it now accounts for approximately 9 percent of UK cases within the last 28 days. It has been also observed in several European countries, including Ireland, Germany, and Denmark.

It is not clear if the two mutations confer a selective advantage to the virus. A222V was first seen in the B.1.177 lineage last year. It was most likely that it originated in Spain, and then spread to northern Europe by holidaymakers.

Many people were skeptical at the time that A222V could confer an advantage. The virus's form, now known as AY.4.2, has been increasing since the Y145H mutation.

This mutation occurs in an "antigenic supersite", a portion of spike protein that antibodies often target and recognize. This part of the spike protein was modified by an antibody once before. It may be contributing to delta's increased ability to escape immunity.

The research is still in preprint so it has not been formally reviewed. We need to therefore be cautious about its conclusions.

It is possible that the Y145H mutation could make the virus more resistant to immunity. This would allow the supersite to be less easily recognized by antibodies.

Contrary to this argument, AY.4.2 is still being used in Denmark, despite its introduction in several European countries. This would indicate that its ability to overcome immunity is not as good as delta's. It could also be that not enough AY.4.2 arrived in these areas for it to take root.

It's still too early to know if this is the beginning or the end of the next dominant lineage. Experimental work must confirm any ability it may have to escape immunity. It's clear that the virus's rise is a sign of the need for continued genomic surveillance.

Matthew Bashton is Senior Fellow in Computational Biology at Northumbria University Newcastle, and Darren Smith is Professor of Bacteriophage Biology at Northumbria University Newcastle.

This article was republished by The Conversation under Creative Commons. You can read the original article.

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