Covid Mutations

[2hats]

Its got a mutation of the spike protein-thing that means the spike is not a perfect match to exisiting antibody-thing, does this equal partial vaccine evasion?

There are huge numbers of variants tweaking the spike all the time. Many of those changes don't amount to any evasion of immunity (some of those changes are not in epitopes targeted by the immune system; some of the changes undermine the viability of the virus). A small number modulate immunity to varying degrees. None of them, thus far, have resulted in any demonstrably significant evasion of immunity in respect of disease. Some may have resulted in small degrees of evasion of immunity to infection.


Perhaps AY.4.2 is merely growing as both convenient conditions (no masking, no distancing, get back to school with no vaccination) and a few key helpful events (superspreading - remember that?) have provided it with the opportunity to establish in schoolchildren and they are quite likely the main driver of this 'wave' (or at least one of the main drivers) - CoMix data indicates that children have been associating as per pre-pandemic whilst adult levels are still much lower (though in the last week or so mixing for children has finally dropped somewhat due to the high number of infections in that cohort).

(Note: PHE T&T data which can not account for behavioural confounders. Spot the parents and grandparents of teenagers.)

 

[2hats]

From the ROK, a preprint of a study investigating age-varying susceptibility to delta/B.1.617.2.

A significant difference between the age-specific susceptibility to delta and pre-delta variants (predominately alpha/B.1.1.7) was observed in younger age groups. This rise in susceptibility was highest in the 10-15 year old cohort (almost two-fold), whereas in those aged 50+ this susceptibility rise was fairly flat (at approximately one-fold).

Even after adjusting for both contact pattern and vaccination status, the delta variant of SARS-CoV-2 tends to propagate more easily among children than the pre-delta strains.

DOI: 10.2139/ssrn.3951778.

 

[2hats]

It looks like AY.4.2, with around a 3%/day growth advantage over AY.4 (which in turn has about 3%/day over B.1.617.2), could come to dominate in the UK by mid-late December.

New variants to keep an eye on: AY.43 (an early fork of B.1.617.2 with N:9L, ORF1b:829I; significant pools of growth across various W European countries) and AY.46.5 (Orf1ab:A3571V; originally Senegal, now >50% in South Sudan, Uganda, Kenya, Botswana, plus not insignificant numbers in some European countries).

Both have likely been fortuitously seeded in the UK due to the recent uptick in international travel. AY.43 may have up to 3%/day growth advantage over B.1.617.2 whilst AY.46.5 might be around 2%/day. But at these small margins of growth advantage (and with smaller, still establishing, numbers) it is not entirely clear which variant would become contenders to dominate in coming months as happenstance/behavioural factors will likely be the main drivers (none of these sub-lineages has any significant biological advantage, it would appear thus far).

 

[_Russ_]

From the ROK, a preprint of a study investigating age-varying susceptibility to delta/B.1.617.2.

A significant difference between the age-specific susceptibility to delta and pre-delta variants (predominately alpha/B.1.1.7) was observed in younger age groups. This rise in susceptibility was highest in the 10-15 year old cohort (almost two-fold), whereas in those aged 50+ this susceptibility rise was fairly flat (at approximately one-fold).
View attachment 295127

DOI: 10.2139/ssrn.3951778.

Surely the age susceptibility number is hugely skewed by the age differential in Vaccine uptake/delivery in the later period?

 

[2hats]

Surely the age susceptibility number is hugely skewed by the age differential in Vaccine uptake/delivery in the later period?

Even after adjusting for both contact pattern and vaccination status

As per the preprint, they adjusted by age-compartmentalising their model to account for differing vaccine uptake rates across the various age cohorts. They mention potential shortcomings themselves (as any good study should): true v estimated contact patterns, cases v actual infections, asymptomatic cases, waning of vaccine immunity and, indirectly, the influence of child-adult mixing.

 

[2hats]

(Gladstone/UC) By creating non-replicating SARS-CoV-2 virus-like particles (SC2-VLPs) this team were able to probe all of the viral protein VOC mutations individually and assess their contributions to infectivity; most studies having been largely focussed on the spike RBD thus far.

Aside from those already identified in spike (S), which have been noted to facilitate antibody evasion and accelerate cell entry, they also found key mutations in nucleocapsid (N) that improve virus packaging. Those appear to provide for more viral RNA per virion (variously up to 10-50x over earlier type). All the action is around positions 199-203 - for example, N:R203M is found in delta/B.1.617.2. These observations suggest a molecular basis for the apparent improved fitness of recent delta-lineage variants.

Further investigation is required to confirm that this improved packaging is seen in vivo. This SC2-VLP approach could be used to probe all viral proteins (S, N, E, M) and could be useful in helping evaluate potential new antivirals.
DOI: 10.1126/science.abl6184.

More commentary here, and discussion with the authors:

New Method Sheds Light on Why Some SARS-CoV-2 Variants Are More Infectious

Using virus-like particles, researchers find an unexpected explanation for why some coronavirus variants are more infectious.

innovativegenomics.org

 

[2hats]

Might be one to keep an eye on - newly designated AY.4.2.1, which is AY.4.2 with N:S202I and S:V36F. Might have an a growth advantage over AY.4.2 (it appears to be growing as a proportion of AY.4.2 which in turn is still growing as a proportion of B.1.617.2). Geographical data would hint that it has perhaps taken advantage of the Immensa lab debacle.

 

[2hats]

Another variant to file under "keep an eye on". Designated B.1.640 with a novel combination of spike mutations Δ136-144, R346S, N394S, Y449N, F490R, N501Y, P681H - not seen elsewhere - along with alpha-consistent changes in ORF8. Immunological consequences of these in combination is not yet clear.

Spotted in France but also the UK, US, Switzerland and Italy. Some sequences from Congo. It has been around for some time but only recently have numbers started to grow. Diversity might suggest this has taken a hold somewhere else with poor surveillance (perhaps in west Africa).

Covid-19 : un nouveau variant détecté dans une école en Bretagne [Exclusif]

Un nouveau variant a été identifié dans une école du Finistère, en octobre. 24 personnes, dont 18 élèves, ont été contaminées. La situation est maîtrisée, selon l’ARS Bretagne.

www.letelegramme.fr

 

[Supine]

Good (long) lecture on mutations, including future outlook at 38mins.

 

[2hats]

A lot of attention now being focused on B.1.1.529 which has a very large number of mutations in spike (A67V, Δ69-70, T95I, G142D/Δ143-145, Δ211/L212I, ins214EPE, G339D, S371L, S373P, S375F, K417N, N440K, G446S, S477N, T478K, E484A, Q493K, G496S, Q498R, N501Y, Y505H, T547K, D614G, H655Y, N679K, P681H, N764K, D796Y, N856K, Q954H, N969K, L981F; two at the furin cleavage site) and is likely significantly immune evasive. For example, Q498R may confer (or at least be associated with) higher infectivity and increased immune evasion.

Phylogeny might even suggest a possibility of reverse zoonosis at some point.

South Africa appears to be a significant source of cases but, since they have kept delta/B.1.617.2 low of late, it might not have had to compete with it and so might not have a fitness edge elsewhere that delta dominates.

Apparent B/T cell epitope mismatch compared to delta:

Heavily mutated Omicron variant puts scientists on alert

Researchers are racing to determine whether a fast-spreading coronavirus variant poses a threat to COVID vaccines’ effectiveness.

www.nature.com

 

[_Russ_]

Depressing news, it really looks like we have still got years of this shit to get through before it calms down

 

[Supine]

I agree with this 100%. More data required.

 

[_Russ_]

South Africa to be put on England’s travel red list over latest Covid variant

Sod waiting for more data, Im more for the act now approach even if it turns out to be no more of a worry than the already major shit we are in at least in upping some defenses it might
wake up some of the people who think its all over

 

[Aladdin]

A lot of attention now being focused on B.1.1.529 which has a very large number of mutations in spike (A67V, Δ69-70, T95I, G142D/Δ143-145, Δ211/L212I, ins214EPE, G339D, S371L, S373P, S375F, K417N, N440K, G446S, S477N, T478K, E484A, Q493K, G496S, Q498R, N501Y, Y505H, T547K, D614G, H655Y, N679K, P681H, N764K, D796Y, N856K, Q954H, N969K, L981F; two at the furin cleavage site) and is likely significantly immune evasive. For example, Q498R may confer (or at least be associated with) higher infectivity and increased immune evasion.
View attachment 298156
South Africa appears to be a significant source of cases but, since they have kept delta/B.1.617.2 low of late, it might not have had to compete with it and so might not have a fitness edge elsewhere that delta dominates. Phylogeny might even suggest a possibility of reverse zoonosis at some point.

B/T cell epitope mismatch compared to delta:
View attachment 298158
View attachment 298159

Heavily mutated Omicron variant puts scientists on alert

Researchers are racing to determine whether a fast-spreading coronavirus variant poses a threat to COVID vaccines’ effectiveness.

www.nature.com

Ah fuck.

 

[Supine]

Tracking here

 

[2hats]

A lot of attention now being focused on B.1.1.529

Classification of Omicron (B.1.1.529): SARS-CoV-2 Variant of Concern

The Technical Advisory Group on SARS-CoV-2 Virus Evolution (TAG-VE) is an independent group of experts that periodically monitors and evaluates the evolution of SARS-CoV-2 and assesses if specific mutations and combinations of mutations alter the behaviour of the virus. The TAG-VE was convened...

www.who.int

 

[Spymaster]

A lot of attention now being focused on B.1.1.529 which has a very large number of mutations in spike (A67V, Δ69-70, T95I, G142D/Δ143-145, Δ211/L212I, ins214EPE, G339D, S371L, S373P, S375F, K417N, N440K, G446S G447S, S477N, T478K, E484A, Q493K, G496S, Q498R, N501Y, Y505H, T547K, D614G, H655Y, N679K, P681H, N764K, D796Y, N856K, Q954H, N969K, L981F; two at the furin cleavage site) and is likely significantly immune evasive. For example, Q498R may confer (or at least be associated with) higher infectivity and increased immune evasion.

FTFY

 

[2hats]

G446S

FTFY

Unfortunately 446 and friends in the 443-450 loop might be one of the keys to degrees of immune evasion (for at least infection) for this new variant, being as a number of point mutations therein potentially facilitate quite significant degrees of escape from hereto fairly potent class 3 antibodies (which bind outside the ACE2 binding site, in both the pre- and post-fusion states).

Though, as you can see, omicron/B.1.1.529 may well prove to have a good crack at undermining the other two key classes too (there is a fourth class but those antibodies are significantly less neutralising than those in the first three classes).

Perhaps crucially, these have the potential to conspire to clobber a number of commonly deployed monoclonal antibody treatments (and cocktails thereof), with clear implications for some of those unable to benefit from vaccine-induced immunity and subsequent adaptive immunity maturation.

 

[elbows]

Classification of Omicron (B.1.1.529): SARS-CoV-2 Variant of Concern

The Technical Advisory Group on SARS-CoV-2 Virus Evolution (TAG-VE) is an independent group of experts that periodically monitors and evaluates the evolution of SARS-CoV-2 and assesses if specific mutations and combinations of mutations alter the behaviour of the virus. The TAG-VE was convened...

www.who.int

I may as well quote from that.

The B.1.1.529 variant was first reported to WHO from South Africa on 24 November 2021. The epidemiological situation in South Africa has been characterized by three distinct peaks in reported cases, the latest of which was predominantly the Delta variant. In recent weeks, infections have increased steeply, coinciding with the detection of B.1.1.529 variant. The first known confirmed B.1.1.529 infection was from a specimen collected on 9 November 2021.

This variant has a large number of mutations, some of which are concerning. Preliminary evidence suggests an increased risk of reinfection with this variant, as compared to other VOCs. The number of cases of this variant appears to be increasing in almost all provinces in South Africa. Current SARS-CoV-2 PCR diagnostics continue to detect this variant. Several labs have indicated that for one widely used PCR test, one of the three target genes is not detected (called S gene dropout or S gene target failure) and this test can therefore be used as marker for this variant, pending sequencing confirmation. Using this approach, this variant has been detected at faster rates than previous surges in infection, suggesting that this variant may have a growth advantage.

 

[Spymaster]

Unfortunately 446 and friends in the 443-450 loop might be one of the keys to degrees of immune evasion (for at least infection) for this new variant, being as a number of point mutations therein potentially facilitate quite significant degrees of escape from hereto fairly potent class 3 antibodies (which bind outside the ACE2 binding site, in both the pre- and post-fusion states).

Though, as you can see, omicron/B.1.1.529 may well prove to have a good crack at undermining the other two key classes too (there is a fourth class but those antibodies are significantly less neutralising than those in the first three classes).

Perhaps crucially, these have the potential to conspire to clobber a number of commonly deployed monoclonal antibody treatments (and cocktails thereof), with clear implications for some of those unable to benefit from vaccine-induced immunity and subsequent adaptive immunity maturation.

I totally appreciate your knowledge on this and many other topics but often find your posts completely indecipherable. I rely on the responses from others to decode them and I'm probably not the dullest bloke here.

You're a wonderful resource but is there any chance you could summarise (tl;dr) your posts, at the end, for us thickos?

 

[2hats]

I may as well quote from that.

Preliminary evidence suggests an increased risk of reinfection with this variant, as compared to other VOCs.

A couple of data points do not, of course, a sound conclusion make (and no clear data on symptomatic state or, obviously, any disease severity).


Though it wouldn't be all that surprising that at least reinfection is a greater possibility with this rich zoo of spike point mutations.

 

[Supine]

You're a wonderful resource but is there any chance you could summarise (tl;dr) your posts, at the end, for us thickos?

Nobody knows what impact this mutation is having but it’s being scienced to shit by the boffins.

 

[Yossarian]

The "Holy Mother of God" epidemiologist who was issuing dire warnings about COVID in Jan. 2020 seems very worried about Omicron.

 

[elbows]

Nobody knows what impact this mutation is having but its being scienced to shit by the boffins.

Newsnight just had a boffin in the studio who I believe spoke about how he had scared himself silly with some of the detail of this variant, but I need to go back and watch it again as I was preoccupied with dishing up my dinner at the time.

 

[2hats]

is there any chance you could summarise (tl;dr) your posts

TL;DR: the unusually large variety of key mutations in this variant could well lend it degrees of immune evasion. It features a lot of significant mutations (with various roles known to affect immunity to differing degrees) all bundled up in one variant, where previously only some of them were seen in variants of concern.

Nobody knows what impact this mutation is having but its being scienced to shit by the boffins.

Indeed. There is relatively well-informed speculation based on in vitro experiments plus earlier studies of VOCs, with their mutations in other combinations and conformations. The actual implication(s) of them all operating in unison in this VOC will be clarified in coming weeks as 'real world' data are collected and further lab studies conducted.

 

[2hats]

Newsnight just had a boffin in the studio who I believe spoke about how he had scared himself silly with some of the detail of this variant, but I need to go back and watch it again as I was preoccupied with dishing up my dinner at the time.

Immunologist Danny Altmann who is typically fairly measured in his statements and not unreasonable in his evaluations.



He mentioned that:

Moderna have greenlit an omicron vaccine candidate, mRNA-1273.529. They expect to have it ready for clinical testing within 60-90 days.

Novavax have also started work on an omicron targeted version of their vaccine and expect to have that ready for testing and potential manufacture within a few weeks.

Novavax developing vaccine that targets new COVID-19 variant

Novavax Inc said on Friday it had started working on a version of its COVID-19 vaccine to target the variant detected in South Africa and would have the shot ready for testing and manufacturing in the next few weeks.

www.reuters.com

 

[8ball]

Gonna be whack-a-moling for a while...

Props to the South Africans on the transparency and genomics.

 

[2hats]

Similarities between omicron/B.1.1.529 spike and the Rockefeller polymutant spike (PMS20) have been pointed out:


Notably that study found that whilst convalescent only and naive vaccinee sera struggled to neutralise the polymutant, convalescent vaccinee sera was still significantly effective.

By aggregating variant of concern-associated and antibody-selected spike substitutions into a single polymutant spike protein, we show that 20 naturally occurring mutations in the SARS-CoV-2 spike protein are sufficient to generate pseudotypes with near-complete resistance to the polyclonal neutralizing antibodies generated by individuals who are convalescent or recipients who received an mRNA vaccine. However, plasma from individuals who had been infected and subsequently received mRNA vaccination neutralized pseudotypes bearing this highly resistant SARS-CoV-2 polymutant spike, or diverse sarbecovirus spike proteins. Thus, optimally elicited human polyclonal antibodies against SARS-CoV-2 should be resilient to substantial future SARS-CoV-2 variation.

This might suggest a three-dose regimen for non-convalescents, allowing sufficient time for affinity maturation, could be advantageous.

 

[elbows]

I see humanity has been real lucky with the S gene dropout again, as its alternated each time, providing a nice shortcut with which to make new variant assumptions based on standard PCR testing. (Original = no dropout, Alpha = dropout, Delta = no dropout, Omicron = dropout).

 

[cupid_stunt]

Immunologist Danny Altmann who is typically fairly measured in his statements and not unreasonable in his evaluations.



He mentioned that:

Moderna have greenlit an omicron vaccine candidate, mRNA-1273.529. They expect to have it ready for clinical testing within 60-90 days.

Novavax have also started work on an omicron targeted version of their vaccine and expect to have that ready for testing and potential manufacture within a few weeks.

Novavax developing vaccine that targets new COVID-19 variant

Novavax Inc said on Friday it had started working on a version of its COVID-19 vaccine to target the variant detected in South Africa and would have the shot ready for testing and manufacturing in the next few weeks.

www.reuters.com

He's good, especially with the mad professor look.