As soon as you thought all the talk about new COVID variants was over, there is news of another: AY.4.2. But what is it, where does it come from, and should we be concerned?
AY.4.2 is called a “line”. These are names for branches of the COVID evolution tree to illustrate their relationship. They are supervised by the hardworking ones Pango network, a joint team of researchers from the Universities of Edinburgh and Oxford who act as the keepers of the lines and handle the assignment of new lines.
If we go back to April of this year, we can trace back the origins of AY.4.2. Our team in Northumbria works as part of Gear UK – the British consortium that is sequencing the genomes of COVID samples to see how the virus changes – had just sequenced two samples linked to India through travel history.
We knew at the time that the lineage circulating in India was B.1.617, but the cases we investigated did not match it. Variants differ in the different mutations they have in their genetic material, and looking at the mutations in our samples it appeared that in our cases some of the generally accepted mutations from B.1.617 were missing, but also some additional mutations exhibited.
What we reported to our colleagues in Cog-UK was classified the following week as B.1.617.2, one of three main sub-lines of B.1.617 that was later named delta from the World Health Organization.
AY is another evolutionary step from here. As soon as the lettering of a lineage is five levels deep, a new combination of letters is started to avoid the name becoming too long. The AY forms of the virus do not differ significantly from the previous ones, although their labeling is different. They are all sub-lines of the delta.
There are now 75 AY lines identified, each with different additional defining mutations in their genome. One of them – AY.4 – has been growing and powering steadily in the UK over the past few months 63% of new cases in the UK in the past 28 days.
Does AY.4 have an advantage?
We are still not sure whether the mutations of AY.4 offer any real benefit, or whether the increasing frequency of ancestry is simply due to what is known as a. is due “Founder Effect”. This is the case when a subset of viruses is separated from the total virus population and then reproduced in isolation. In the area in which the separated viruses are located, all subsequent viruses will therefore be descendants of this subgroup.
In the case of COVID, this could have happened in a single case at a major event. This lonely virus would be the “founder”, the only virus that spread at the event. If a significant number of people became infected who later infected others, it can quickly accumulate a large amount of viruses of the same origin. For a particular form of virus to dominate, it sometimes doesn’t have to be better than others – it just has to be in the right place at the right time.
However, given its increasing dominance in the UK, AY.4 could well have a selective advantage. The key change in AY.4 is the A1711V mutation, which affects the virus’ Nsp3 protein, which plays a number of roles in virus replication. However, the effects of this mutation are unknown.
This brings us to AY.4.2 – a subline of AY.4 – which was first mentioned in late September, although it appears to have surfaced in the UK in June. It is defined by two additional genetic mutations, Y145H and A222V, that affect the spike protein. the Spike protein is an important part of the virus’s outer surface and is the part of its structure that it uses to invade cells.
The volume of AY.4.2 has grown steadily to the point where it matters now about 9% of cases in the UK in the past 28 days. It has also been observed in a few European countries: Denmark, Germany, and Ireland to name a few.
It is also unclear whether its two mutations offer the virus a selection advantage. A222V was already seen in the B.1.177 line last year, the probably originated in Spain and was then spread across Northern Europe, most likely by vacationers. Back then, many were skeptical that A222V would give an advantage. In fact, in the form of the virus known as AY.4.2, the increase appears to have only appeared since its Y145H mutation.
This mutation resides within an “antigenic supersite” of the spike protein – a part of the protein that antibodies often recognize and attack. We know that this part of the spike protein has already been changed once by a mutation in Delta’s genetic material, and that this is it may contribute to delta’s better ability to escape immunity as it makes it harder for antibodies to attack. However, the research examining this is still in the preprint, which means it has yet to be formally reviewed – so we need to treat its results with caution.
However, it is possible that the Y145H mutation gives the virus an even greater ability to escape immunity by making this overlay less noticeable to antibodies.
The counter-argument is that AY.4.2 has not caught on despite its introduction in several European countries and has disappeared from the radar in Germany and Ireland – although it lingers in Denmark. This would suggest that his ability to bypass immunity is no greater than Delta’s. Likewise, it could be that not enough AY.4.2 arrived at these locations to catch on.
Really, it’s too early to tell if this is the start of the next dominant line. Any ability to escape immunity must be confirmed by experimental work. However, the emergence clearly shows that genomic surveillance of the virus is still required.