Covid Mutations

[2hats]

Might have been a (as yet unassigned) sub-lineage of BA.2 with Orf3a:H78Y and nuc:C22792T (seen in a few places across northern Europe). It's not clear thus far that it has any particular advantage.

 

[elbows]

Yes H78Y was mentioned in the now-deleted tweet.

 

[2hats]

The latest UK epidemiological data (UKHSA, technical briefing 39) suggests omicron recombinant XE (BA.1 plus BA.2) might have a small growth advantage over BA.2, which could see it come to dominate in the UK later this year (assuming no new VOC usurps it).

The XE recombinant contains BA.1 mutations for NSP1-6 and then BA.2 mutations for the remainder of the genome. As of 22 March 2022, there are 763 XE sequences in the UK data. As of 22 March 2022, there are 637 XE cases in England. These are geographically distributed across England and increasing in number, with the first case detected via sequencing on 19 January 2022, and most cases in East of England, London, and the South East.

The median growth rate is +9.8% per week.

 

[elbows]

I note that zahir linked to an article about BA.4 and BA.5 in the worldwide thread. #10,754

Latest UKHSA report doesnt have all that much to say about those from a UK context yet, their ability to analyse is still more geared towards XE, but they do say this:

https://assets.publishing.service.gov.uk/government/uploads/system/uploads/attachment_data/file/1067672/Technical-Briefing-40-8April2022.pdf

Two new variants were identified as part of horizon scanning on 4 April 2022. Work is underway to precisely define the phylogeny of these variants. These have been designated as lineages BA.4 and BA.5 and classified by the VTG on 6 April 2022, as V-22APR-03 and V-22APR-04, respectively.

V-22APR-03 shares all mutations/deletions with the BA.2 lineage except the following: NSP4: L438F reverted to WT (wild type); S: 69/70 deletion, L452R, F486V, Q493 (WT); ORF 6: D61 (WT); ORF 7b: L11F; N: P151S. The spike 69/70 deletion will result in an undetectable S-gene target (S-gene target failure) in the Taqpath assay.

The earliest BA.4 sample in GISAID was from South Africa with a sample collection date of 10 January 2022. However, Figure 8 shows the accumulation of genomes and geographic spread is more recent. Countries reporting BA.4 genomes via GISAID now include South Africa (41 genomes), Denmark (3), Botswana (2) and England and Scotland reporting one each. Although the number of total genomes is small, the apparent geographic spread suggests that the variant is transmitting successfully.

BA.5 shares the same mutations/deletions as BA.4 except the following: M: D3N; ORF 7b: L11 (WT); N: P151 (WT); synonymous SNPs: A27038G, and C27889T.

Currently there are 27 sequences reported with this lineage, all from South Africa. This lineage shows sample dates between 25 February and 25 March 2022 (Figure 9).

 

[2hats]

New omicron variants BA.4 and BA.5 detected in South Africa (small numbers already also seen in Botswana, Denmark, Germany, Austria, Belgium and the UK).

Key amino acid mutations include S: L452R, S: F486V, ORF7b: L11F*, N: P151S* and nuc: G12160A relative to BA.2.

In more detail:
BA.4 (spike) - T19I, G142D, G339D, S371F, S373P, D405N, K417N, N440K, L452R, S477N, T478K, E484A, F486V, N501Y, D614G, N679K, p681H, N764K, D796Y, N969K; nucleotide mutations G12160A , 9866C, G27788T.
BA.5 - G142D, V213G, G339D, S371F, S373P, S375F, T376A, K417N, N440K, S477N, T478K, E484A, F486V, Q498R, N501Y, Y505H, D614G, N679K, p681H, N764K, D796Y, Q954H, N969K; nucleotide mutations G12160A, 9866C, 27259A.

Both typically feature the 69/70 deletion (think SGTF dropout). At present no evidence in South Africa that these variants lead to significant increases in hospitalisation or death (caveats: bear in mind local demographics and antigenic exposure history).

S: F486V in particular may lend BA.4 and BA.5 an even greater degree of escape from vaccine (and none-omicron-infection) elicited neutralising antibodies than previous omicron amino acid changes (it is right in the sweet spot for previously computed potential antigenic escape sites). This ongoing evolution (much faster than the fastest known seasonal flu type) away from first generation vaccine immunity coverage may prove to be a trigger for a vaccine update in the direction of this antigenic drift.

WHO says it is analysing two new Omicron COVID sub-variants

The World Health Organization said on Monday it is tracking a few dozen cases of two new sub-variants of the highly transmissible Omicron strain of the coronavirus to assess whether they are more infectious or dangerous.

www.reuters.com

 

[Aladdin]

When is this going to end?

 

[elbows]

When is this going to end?

Three different interpretations of 'end' to consider:

In terms of the virus vanishing or becoming 100% irrelevant to public health, no end is expected. For example, even beyond the acute pandemic phase, we are to expect to have to manage seasonal waves of the virus and ongoing vaccination campaigns tied to expectations about those waves.

In terms of the acute phase of the pandemic and really heavy policies that have a large and obvious affect on everyones lives, we are already over a year into countries like the UK striving to get beyond that, with somewhat mixed results so far. If we ignore the ongoing deaths and health service pressures, then they have already 'succeeded', and we can also observe attitude changes on forums like this one which give the impression that a big chunk of that mission is already completed. However caveats remain, bringing me to the following description of third sort of 'end':

In terms of the rapid mutation of the virus in ways that keep heavier concerns on the table, potentially causing multiple waves per year which are not restricted to standard seasonal pattern assumptions, expectations still feature plenty of guesswork. The likes of Vallance a few months ago made it sound like the default assumption is that several more years of this are plausible before things might start to slow and settle. But there are many factors, and the implications of each new variant will vary. Countries also have some divergence in the timing and nature of their population immunity picture, which may in some cases have quite a large impact on the waves seen as a result of particular new variants.

It would certainly have been easier for me to declare an end to the acute phase of the pandemic if there had been a clear period where the mutation picture was more settled, resulting in a much larger gap between waves. Without that we have a messy situation where I can see why plenty of people think the acute phase of the pandemic is over, but where I cannot bring myself to draw the same conclusion. The vaccine era has made a big difference to the required policy responses, but has also enabled situations which ensure there are plenty of opportunities for the virus to continue its evolution at blistering speed, and with the impetus to do so.

 

[Aladdin]

Three different interpretations of 'end' to consider:

In terms of the virus vanishing or becoming 100% irrelevant to public health, no end is expected. For example, even beyond the acute pandemic phase, we are to expect to have to manage seasonal waves of the virus and ongoing vaccination campaigns tied to expectations about those waves.

In terms of the acute phase of the pandemic and really heavy policies that have a large and obvious affect on everyones lives, we are already over a year into countries like the UK striving to get beyond that, with somewhat mixed results so far. If we ignore the ongoing deaths and health service pressures, then they have already 'succeeded', and we can also observe attitude changes on forums like this one which give the impression that a big chunk of that mission is already completed. However caveats remain, bringing me to the following description of third sort of 'end':

In terms of the rapid mutation of the virus in ways that keep heavier concerns on the table, potentially causing multiple waves per year which are not restricted to standard seasonal pattern assumptions, expectations still feature plenty of guesswork. The likes of Vallance a few months ago made it sound like the default assumption is that several more years of this are plausible before things might start to slow and settle. But there are many factors, and the implications of each new variant will vary. Countries also have some divergence in the timing and nature of their population immunity picture, which may in some cases have quite a large impact on the waves seen as a result of particular new variants.

It would certainly have been easier for me to declare an end to the acute phase of the pandemic if there had been a clear period where the mutation picture was more settled, resulting in a much larger gap between waves. Without that we have a messy situation where I can see why plenty of people think the acute phase of the pandemic is over, but where I cannot bring myself to draw the same conclusion. The vaccine era has made a big difference to the required policy responses, but has also enabled situations which ensure there are plenty of opportunities for the virus to continue its evolution at blistering speed, and with the impetus to do so.

Do you think that the very high risk/ very immunosuppressed will have to take their chances at some stage?

 

[elbows]

Do you think that the very high risk/ very immunosuppressed will have to take their chances at some stage?

Quite a few already have, or have effectively been placed in that situation without much say in the matter, due to the behaviour of others, the rules, institutional failures etc. And government policy has certainly shifted the burden onto those groups in particular.

I dont really have a tidy answer because there are so many factors. To mention just a few, when it comes to individual cases there are often differences between how much risk they are perceived to face from the virus, and what will actually turn out to happen to them if they catch it. But that features a lot of unknowable things and plenty of people still arent keen to find out. But just by living in this country they've already faced a certain degree of risk, especially these days. They should certainly try to be setup to receive the particular treatments that are available to take in the first days of COVID. If I were them I would adopt a different attitudes during times of ridiculously high prevalence, but those periods have been rather prolonged in this country. And what sort of balancing act makes sense in that regard depends on other aspects of their lives and how much of an enjoyable existence they can have when continuing to avoid all sorts of risky situations.

Personally if I had been in an especially vulnerable group then my attitude would largely come down to basing my behaviours and risk-taking on a combination of my mental health and the levels of infection present in society at particular moments in time. The traditional sort of view about what the normal state of affairs of living with this virus forever more should look like in future absolutely does not feature the huge levels of infection we've had in this country at the moment. Those things are supposed to happen occasionally, not all year round, and those are the times when people should take more precautions that affect their lives more notably. There should be other periods where levels of infection are much lower, and vulnerable people should be able to do more without taking such a big risk. The problem is that by experiencing a big Delta wave that dragged on straight into a huge Omicron wave and then yet another huge Omicron wave, those periods have not exactly been a useful part of the UK scene in recent memory. So its all very well me pinning my hopes on a period of far less risk coming soon, but I cannot promise it. And in the meantime more vulnerable people have either deliberately decided to take more risks, or have got the wrong impression based on the extent to which the current giant wave has been normalised in this country, or have been placed in harms way without having much influence on it, or have successfully shielded themselves. And some vulnerable people have caught it without the worst possible consequences coming to fruition, which may have pleasantly surprised them and changed their attitude about future risk. For some that change in attitude will serve them well, for others it may yet have sealed their fate in future. But I suppose that sort of thing is after all always a part of life, and there is going to be a lot of variation in terms of how these thoughts and behaviours evolve in individuals in future, and whether they are happy about it or feel let down, forgotten and doomed.

 

[teuchter]

Obviously the question of whether high risk people "have to take their chances at some stage" is a difficult, and loaded, one but it's a very important one too.

It seems to me that it's important to try and help people take that decision in a well informed way.

I've no argument with the fact a general "it's all over now, get over it" attitude is unhelpful and potentially dangerous.

But sometimes I also get the feeling that there's some kind of avoidance of reality amongst many, who are unwilling to accept that things may not get much better than they are now. Sometimes this view is partly connected to anger about the ways in which the pandemic has been dealt with so far, and a feeling that we shouldn't be in this position in the first place, or a general feeling that other people's attitudes (whether govt or population) are overly reckless. Those people will readily jump on any comments suggesting that things have now changed such that a change in attitude is not unreasonable, and I wouldn't be surprised if I get some responses to this post along those lines.

I think they may be leading some people into a false impression that at some point it will be "over" and everyone will be safe from risk. And I fear that will mean some people will waste away a portion of their life - maybe even the remainder of their life - waiting for something that will never come.

Everyone needs to make their own decision based on how much they value various activities, and taking into account all the stuff elbows says above about periods of higher and lower prevalence, but with a realistic idea of the likelihood of risk ever approaching something like zero.

I'm lucky enough that as far as I know, I'm not in a high risk group, and therefore have been able to make a decision to return to something like "normal" without that meaning a great leap in risk for me personally. Like many people, of course I am close to people who are at higher risk, such as elderly parents. Most of them seem to have taken the decision that they'd rather get on with things now, even if they know this puts them at greater risk. I take my lead from them - unlike this time last year, I am not actively discouraging them from doing things that mean mixing with large numbers of people (even if it still worries me a bit). That's not just because the picture has been changed by vaccination, but because the prospects of things getting very much better in the coming months or years don't look all that great.

 

[elbows]

But sometimes I also get the feeling that there's some kind of avoidance of reality amongst many, who are unwilling to accept that things may not get much better than they are now.

That's not just because the picture has been changed by vaccination, but because the prospects of things getting very much better in the coming months or years don't look all that great.

I must have missed the memo about that tidy version of reality you are presenting. The fact is there is considerable uncertainty, as your own words indicate via phrases like 'may not get much better'. When unknowns are involved, is it really fair to describe attitudes as being an avoidance of reality? Surely a proper sense of reality involves accepting the extent to which unknowns are involved, and that those unknowns then affect the implications of what 'avoiding that reality' actually are as far as you are concerned?

What you've said there points to some themes that at least have enough sense in them that I think it at least warrants further discussion. And there hasnt really been enough discussion of many of the details that will determine what the future actually ends up looking like, so we should indulge in a bit of that now.

For a start, lets examine when the moment of maximum 'as good as its going to get' was reached in your mind. Please do tell us when that was exactly. Because to my mind, the situation is always evolving, and I am prepared to list a bunch of examples of things past, present and future which had or have the potential to change the picture for better or worse:

Some things that changed recently or at least within the last 6 months, making the situation better than it was previously:

• Some possible weaknesses in Oxford Astrazenica vaccine protection were compensated for by way of mRNA booster shots. Especially useful stuff given the number of older people who'd previous only had AZ vaccine in this country. And/or boosters in their own right may turn out to have an advantage that doesnt wane all the way back to insignificant.
• Vaccination became available for younger people, ie children.
• More treatments became available/the mechanisms by which vulnerable people could get access to them were formalised.
• Natural immunity levels were boosted.
• We had some luck in terms of certain properties of the variant that came to dominate.

Some things that could change in future that improve the situation:

• The rate of mutation could decrease, leading to a longer gap between waves. Or the virus may exhaust the sorts of changes it can use to massively increase transmissibility, likewise certain other properties.
• More treatments could become available.
• Additional vaccine doses could increase deeper levels of protection.
• Vaccines could be updated to better match current variants.
• Vaccines could become available that do far more to reduce infection and transmission.
• Overall levels of immunity could reduce the size of waves comapred to the monster waves we've had recently.
• Protection from severe disease may continue to grow on an overall population level.
• We may learn more about how to identify exactly who is at most risk of the worst implications of the disease.

Some things that could change in future that make the situation worse:

• We mess up the timing of a much needed booster dose at some point.
• The virus mutates around the current vaccines to a much greater extent, and we mess up the timing of mass supply of updated vaccines.
• The virus mutates to become more deadly, eg sending the rates of people who need mechanical ventilation back up again.
• The virus mutates in a manner that changes the age-risk profile in a very unhelpful way.
• Some treatment options become less effective, eg via the virus mutates around the protection they offer, in a manner not entirely dissimilar to anti-biotic resistance. This is already monitored for and one example has probably already been spotted in the UK. I'll talk about this more in another post.
• We discover that repeated vaccination beyond the initial 3 or 4 doses has diminishing returns.
• Politics and public attitudes robs us of some of the behaviour-based protections we previously relied on during difficult moments, and makes policy timing and strength even worse than earlier failings.
• Some realities of the long-term health consequences become more apparent in ways that really upsets the apple cart and some of the cold calculations used to justify a return to relative normality, causing much woe and political mess.

Those lists arent supposed to be exhaustive, just some examples. Combined, I do not have a clear sense of the recent situation being 'as good as it gets'. I also do not know whether conventional wisdom about the viruses evolution settling down within a few years and getting us into more a a typical seasonal pattern of disease will come to full fruition. But it might, and if it does then I wont need to use the word pandemic any more in relation to this virus, and I will be able to evolve my attitudes and recommendations quite far beyond the extent that I've been able to in the last two years.

 

[elbows]

Also dont forget that if we take the extremely long-term view that extends beyond the window of our own lifetimes, there is another way to consider things:

Eventually everyone is exposed to the virus when they are still rather young. This is one of the ways by which the implications for humanity of a virus can change a lot even if the virus itself remained consistent. Especially when the worst consequences of a virus occur when people are exposed to it for the first time only in old age.

 

[teuchter]

For a start, lets examine when the moment of maximum 'as good as its going to get' was reached in your mind. Please do tell us when that was exactly.

That's not a moment that's been reached in my mind, and it may never be, because of all the uncertainty you describe.

It would perhaps be better to call it a point of diminishing returns, and that point will be different for everyone.

For me, there is some point at which the length of time waiting, vs. the likelihood of things changing substantially during that time, reaches some kind of ratio where I decide to cut my losses. That point is not in any way scientific or precise; it's the result of trying to weigh up various judgements about multiple factors, and the relevant point is also different according to different activities.

 

[elbows]

Makes sense, and I have no problem with individual judgements around the concept of diminishing returns.

I did gear myself up to be ready for possibly reaching that sort of state during Omicron, especially after booster dose, but in the end the sheer size of UK Omicron waves got in the way of my own personal calculations reaching that destination. I've ended up slightly nearer to that destination by virtue of my diabetic brother and diabetic nephew having had Covid this year, but the journey for me remains incomplete. I still expect that regardless of where my own journey takes me next, there will come a point in the next two or three years where changes to viral evolution pace and wave timing really alters my sense of where things are at. But I'll only know I'm at such a destination after a lengthy period of waiting for hindsight to kick in reliably. In the meantime I really need some gaps between waves to recharge my batteries in other, less permanent ways.

 

[2hats]

Preliminary work (awaiting a preprint) would appear to suggest that omicron BA.5 (likely driving the incoming UK 'wave'), in contrast to BA.1/BA.2, has switched tropism back again and is once more leveraging TMPRSS2 (lower respiratory tract) for cell entry, perhaps providing scope for syncytia formation. Elevated pathogenicity could be anticipated as a result, though obviously, with more extensive vaccine-mediated immunity, this will play out differently to earlier pre-omicron waves.

Separately, recent work at Imperial, investigating a pseudovirus recombinant of omicron BA.1 spike with a delta-like S2 subunit (key part of the cell fusion apparatus) has already hinted at the potential for new omicron and future variants to gain increased pathogenicity.
DOI: 10.1101/2021.12.31.474653v2.

Further work by the same group identifies BA.4 and BA.5 as both being antigenically distinct from BA.1 and, to a lesser extent, BA.2, though the enhanced breadth of neutralisation observed following breakthrough infection with omicron would suggest that a multivalent WT/omicron booster strategy could be a viable route forward.
DOI: 10.1101/2022.05.25.493397.

Also, (Hokkaido) other animal model work suggests BA.4/BA.5 are more fusogenic in lung cells, and potentially more pathogenic (than BA.2/BA.1).
DOI: 10.1101/2022.05.26.493539.

Additionally, antigenic analysis from Columbia (NY) points to BA.4 and BA.5 improving evasion of class 1, 2 and 3 antibodies (compared to BA.1, BA.2 and BA.2.12.1).
DOI: 10.1101/2022.05.26.493517.

 

[2hats]

Currently there are BA.4 sub-lineages BA.4.1, BA.4.1.1 and BA.4.1.2 (mostly seen so far in SA, Germany and Austria).

BA.5 sub-lineages are BA.5.1 (dominating the ongoing wave in Portugal), BA.5.2 & BA.5.2.1 (both in SA, UK, US), BA.5.3 (SA, Germany), BA.5.3.1 (SA, Austria, UK) and BA.5.5 (US).

Sequencing in the UK might suggest BA.5.1 is racing up the charts (though more data is required to be certain). Mutations in ORF3a/10 possibly improve innate immunity evasion and/or increase asymptomatic episodes leading to more rapid, cryptic spread (clearly has the potential to elevate the risk to vulnerable groups).

​

 

[elbows]

Thanks for keeping us up to date with these developments.

 

[RD2003]

Yes, thanks. But what does all this mean in practical terms?

 

[elbows]

Yes, thanks. But what does all this mean in practical terms?

Its not that easy to give a straightforward answer to that. The sort of answers I might be comfortable coming out with at this stage tend to wind some people up, they may moan that its a load of useless waffle. But thats just the nature of things at this stage, its a tug of war between viral evolution and the fact we arent talking about immune naive populations anymore, lots of immunity has built up via vaccination and prior infection.

Things I am still quite comfortable claiming at this stage include:

Some degree of complacency can be gotten away with these days, but quite how much is still uncertain. Authorities are pretty determined to test quite how far they can push this, but despite what they say publicly they cannot really be completely certain that there will be no need to step backwards with their approach at any future point.

Its a good thing experts are still paying attention to the evolution of the virus, and to any data that can provide early warnings if the protection against hospitalisation etc wanes notably, or is evaded by changes to the virus.

Simplistic ideas that the virus will always evolve in a milder direction, eg one that leads to less cases requiring mechanical ventilation like we saw with several versions of Omicron, are unsafe and cannot be relied on to hold true in future.

The people that a year ago tried to support a particular agenda by suggesting things would quickly stabilise and that there would soon be an end to frequent large waves due to 'endemic equilibrium' were full of shit.

Changes to our immunity or to the virus which leads to more asymptomatic cases for longer, has implications for the ability to shield those who remain vulnerable.

Fatigue and a desire to move on has hugely diminished the appetite for sufficient journalists, politicians, medical experts and the public to sustain serious discussions about the complexities and practicalities of 'learning to live with covid' in the short, medium and long term.

Experts and officials including the likes of Vallance who went on about the pandemic not being over yet, and estimated at least a few more years before things might settle down, were taking a stance that is compatible with what we've seen in regards contiued evolution of the virus so far. The likes of Javid, claiming we are beyond the pandemic in this country, are full of shit. But the detail of how the virus evolves and how the immunity picture evolves will determine the extent to which this actually ends up mattering in practical terms over the next year or two.

The minimum that people should reasonably expect is that the evolution of the virus still has the potential to cause large enough waves that enough people get simultaneously sick with covid that there is some disruption to society/everyday life. But its still not so easy to predict the magnitude of coming waves, or the extent to which such things will spill beyond disruption, and into more severe implications for some peoples health and the ability of healthcare systems to cope.

Existing population immunity makes it unlikely that even under worst case scenarios, we end up with a situation equivalent to going all the way back to square one. Ultimately I still hold 'never say never' in reserve, but there is nothing at this time which would cause me to travel all the way back to what some would view as 'peak doom mongering'.

 

[elbows]

Oh one more:

Its understandable that those who are horrified by the continuing global vaccine inequality try to make the case that the large unvaccinatied populations are driving viral evolution. However this doesnt really ring true to me because surely both 'population immunity via prior infection' and 'population immunity via vaccination' both provide impetus (selection pressure) for the virus to evolve in order to evade immunity and find sufficient fresh victims. And there has hardly been a shortage of new cases in heavily vaccinated populations such as the UKs. So, with the current vaccines at least, I cannot make that stance work, and would rather focus on the need to vaccinate everyone in order to reduce their chances of hospitalisation and death, rather than claiming that a vaccinated planet will fix the covid evolution woes or slow the pace of viral changes.

 

[2hats]

BA.5 is destined to become the dominant variant in the UK in the coming month (now clearly outgrowing BA.4 as well as all previous); similar relative growths seen in the US.

​

Some eyes are on BE.1 (± various mutations) which might have a growth advantage over even BA.5.

 

[2hats]

New kid on the block - could be growing rapidly, geographically (Australia, Canada, Germany, NZ, UK) originally spotted in India - BA.2.75 with a significant number of spike mutations (and what could be contributions to innate evasion in ORF):

S:K147E, W152R, F157L, I210V, G257S, D339H, G446S, N460K, R493Q​

ORF1a:S1221L, P1640S, N4060S​

ORF1b:G662S​

E:T11A​

Data thus far suggest a growth advantage over even BA.5 (though 'health warning': very early days, founder effect, etc).

Spoiler: Growth advantage: take this with a pinch of salt.

 

[2hats]

There might be hints of BA.5.x beginning to falter, as it increasingly struggles to find sufficient susceptibles over the coming fortnight.

​

Fear not though as BA.2.76 (BA.2 with S:R346T and S:Y248N - appears to be a key combination) looks like it could be limbering up in the wings, fresh from a tour of India.

​

 

[2hats]

There might be hints of BA.5.x beginning to falter, as it increasingly struggles to find sufficient susceptibles over the coming fortnight.

The MRC Biostatistics Unit (Cambridge) suggests that, for England, the current wave will peak in the week 17th-23rd July.

National Rt estimated to be 1.26, though in the NE and London it is now estimated to be <1.
85% of the population are estimated to have been infected at some point and 21% suffered reinfections.

 

[2hats]

(UCL/Crick/MRC-Glasgow) In vitro indication that BA.4, and particularly BA.5, have significantly improved evasion of innate immunity.

Here, we demonstrate that the most recent Omicron variants have enhanced capacity to antagonise or evade human innate immune defenses. We find Omicron BA.4 and BA.5 replication is associated with reduced activation of epithelial innate immune responses versus earlier BA.1 and BA.2 subvariants. We also find enhanced expression of innate immune antagonist proteins Orf6 and N, similar to Alpha, suggesting common pathways of human adaptation and linking VOC dominance to improved innate immune evasion. We conclude that Omicron BA.4 and BA.5 have combined evolution of antibody escape with enhanced antagonism of human innate immunity to improve transmission and possibly reduce immune protection from severe disease.

​

DOI:10.1101/2022.07.12.499603.

 

[2hats]

Variants to keep an eye on - BA.2.75 or a sub-lineage thereof with S:R346T, or perhaps a BF.x lineage (BA.5 sub-lineages) with BF.7 (also sporting R346T, amongst others) being a favourite. R346T is one of the largest known RBD escape mutations, also conferring both increased ACE2 binding and RBD expression (relative to recent omicron lineages).

Modelling might suggest one of those coming to dominate infections and perhaps drive a new UK wave around October-November (coincident with waning circulating immunity across the population and significant behavioural change).

​

 

[2hats]

Add BA.2.75.1 (defining mutation S: D574V) to that list. It might start driving an autumnal wave earlier (second half of September).

BL.1 (essentially BA.2.75.1+S:R346T) is another, with potential, to perhaps keep an eye on.

Both initially spotted in India.

 

[elbows]

Add BA.2.75.1 (defining mutation S: D574V) to that list. It might start driving an autumnal wave earlier (second half of September).

Some of the remaining data (eg from ZOE) implies a.possible bottoming out of figures and the first signs of an increase in places like Scotland that are ahead of England in terms of school holiday timing etc, and the picture is mixed in different regions of England too. But I am making this remark prematurely, its too early to tell whether its the first signs of a resurgence or just some less significant fluctuations. I certainly wont be surprised if the next wave comes sooner than previous suggestions implied, and more like the timing you've mentioned there. But hopefully I'll be wrong about that, the relentless wave cycle we've endured so far is not what the establishment were banking on when they came up with their do little plans. I'm pretty sure they were banking on less waves per years than we've ended up with, with longer recovery periods in between them. I dont think the immunity and evolution picture we've been seeing is really compatible with assumptions they've used as a policy foundation, the population immunity picture has not so far been able to replicate the sort of gaps between waves that lockdowns induced earlier in the pandemic. The sort of justifications like 'endemic equilibrium' that were routinely spouted to the press a year or so ago but turned out to be a poor fit with reality, have been replaced with silence rather than anything of substance.

 

[2hats]

Also should point out that BA.2.75.2 (BA.2.75 with S:R346T, S:F486S, S: D1199N ), just designated this week, is quickly ticking up in several countries (India, Chile, England, Singapore, Spain, Germany, South Korea, Australia, US) and must also be in the running.

 

[Indeliblelink]