Covid Mutations

[2hats]

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

To follow up on this...

Tracking here

The long phylogenetic branching (recent emergence with a distant recognisable ancestor) could suggest either periods of extended incubation in immune suppressed individuals, or a long period of evolution beyond the scope of adequate genomic surveillance, or spillback (reverse zoonosis), or combinations (and multiple episodes) thereof.

The heavy clustering of mutations in a quite focused region of spike, namely S1 (RBD in particular), might suggest a history of adaptation to optimise for other ACE2 (or just other) receptors in another species. However the appearance of short RNA sequences (RNA insertions) from human genes would suggest human host (though that in itself doesn't entirely rule out cross-species evolution).

 

[existentialist]

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.

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

It's like it's playing with us...

 

[2hats]

In Gauteng province, SA, the region omicron/B.1.1.529 was first identified there, notably hospital admissions have significantly jumped (around 3-fold in the last couple of weeks) whilst they are pretty much flat elsewhere in the country. Similarly, wastewater viral copies now rapidly climbing to levels previously seen in their summer 'wave' which was largely driven by delta/B.1.617.2.

 

[elbows]

Thanks for that info. I was looking for that sort of data yesterday because I didnt buy into the words of the doctor on telly about cases being mild, but I failed to find the right website. Do you have a link?

 

[2hats]

NICD data sources.

 

[Supine]

Looks like s gene drop out won’t be a reliable method if detection. It’s already back in some branches.

 

[2hats]

hospital admissions have significantly jumped (around 3-fold in the last couple of weeks)
View attachment 298683

Now almost 5-fold as reporting catches up.

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 Q493R, 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.

Correction: Q493R not Q493K. Am very disappointed that spy didn't pick that one up.

 

[existentialist]

Now almost 5-fold as reporting catches up.

Correction: Q493R not Q493K. Am very disappointed that spy didn't pick that one up.

He's had his eye off the ball for a while now....

 

[elbows]

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

I didnt realise that he is part of Indie SAGE these days, and featured in todays stream.

 

[2hats]

(nference, MA) A preprint of a comparative mutational analysis of omicron with other HCoV suggests it exhibits signs of recombination with a common cold coronavirus, possibly HCoV-229E (though there are other potential candidates, eg HCoV-OC43, HCoV-NL63).

We compared the mutations of Omicron with prior variants of concern (Alpha, Beta, Gamma, Delta), variants of interest (Lambda, Mu, Eta, Iota and Kappa), and all 1523 SARS-CoV-2 lineages constituting 5.4 million SARS-CoV-2 genomes. Omicron’s Spike protein has 26 amino acid mutations (23 substitutions, two deletions and one insertion) that are distinct compared to other variants of concern. Whereas the substitution and deletion mutations have appeared in previous SARS-CoV-2 lineages, the insertion mutation (ins214EPE) has not been previously observed in any SARS-CoV-2 lineage other than Omicron. The nucleotide sequence encoding for ins214EPE could have been acquired by template switching involving the genomes of other viruses that infect the same host cells as SARS-CoV-2 or the human transcriptome of host cells infected with SARS-CoV-2. For instance, given recent clinical reports of co-infections in COVID-19 patients with seasonal coronaviruses (e.g. HCoV-229E), single cell RNA-sequencing data showing co-expression of the SARS- CoV-2 and HCoV-229E entry receptors (ACE2 and ANPEP) in respiratory and gastrointestinal cells, and HCoV genomes harboring sequences homologous to the nucleotide sequence that encodes ins214EPE, it is plausible that the Omicron insertion could have evolved in a co-infected individual. There is a need to understand the function of the Omicron insertion and whether human host cells are being exploited by SARS-CoV- 2 as an ‘evolutionary sandbox’ for host-virus and inter-viral genomic interplay.

DOI: 10.31219/osf.io/f7txy.

TL;DR:

Omicron variant may have picked up a piece of common-cold virus

The Omicron variant of the virus that causes COVID-19 likely acquired at least one of its mutations by picking up a snippet of genetic material from another virus - possibly one that causes the common cold - present in the same infected cells, according to researchers.

www.reuters.com

 

[2hats]

Taxonomical news...

Omicron/B.1.1.529 has now been split into two related lineages. BA.1 is the original variant whilst BA.2 exhibits quite a number of mutational differences: predominately in ORF1ab, whilst having 5 less mutations in spike (but all mutations in RBD common). Most notably it does not have the (spike) 69-70 deletion and as a consequence this is S gene positive (can not be inferred from the PCR SGTF drop out alone). Sequencing has spotted BA.2 in South Africa, Australia and Canada thus far (small numbers).

 

[2hats]

Some thoughts on the evolutionary directions that future variants might take and what that might mean practically - for example, seasonal epidemics, or perhaps largely becoming a virus of children.

Beyond Omicron: what’s next for COVID’s viral evolution

The rapid spread of new variants offers clues to how SARS-CoV-2 is adapting and how the pandemic will play out over the next several months.

www.nature.com

 

[8ball]

Some thoughts on the evolutionary directions that future variants might take and what that might mean practically - for example, seasonal epidemics, or perhaps largely becoming a virus of children.

Beyond Omicron: what’s next for COVID’s viral evolution

The rapid spread of new variants offers clues to how SARS-CoV-2 is adapting and how the pandemic will play out over the next several months.

www.nature.com

I read that as “a virus of chickens”. Which raised eyebrows as well as striking me as somewhat optimistic.

 

[2hats]

Preliminary variant T cell study from LJI (Sette). Initial analysis of the entire SARS-CoV-2 proteome indicates 88% of CD4+ and 95% of CD8+ T cell epitopes are conserved in omicron/B.1.1.529. In spike (ie the target of most approved mRNA/viral-vector/protein vaccines) 72% of CD4+ and 86% of CD8+ epitopes are conserved. Anticipates some degrees of additional preservation of immunogenicity through cross-reactivity. Verification through experimental lab work is under way.

Source: thread.

 

[2hats]

Deep mutational scanning* (note: not laboratory experiments) suggests that omicron/BA.1 (B.1.1.529.1) could have an advantage over omicron/BA.2 largely due to the presence of G446S (missing from BA.2).

Additionally, a sub-variant of BA.1 has been popping up with the additional point mutation S:R346K (around 10% of sequences thus far). R346K was previously seen to convey degrees of escape in mu/B.1.621. The same deep scanning technique would suggest that BA.1+S:R346K has an advantage over the parent and even the Rockefeller PMS20 polymutant (post #352).

* DOI: 10.1101/2021.12.04.471236.

Separately, a new omicron sub-lineage, BA.3, appears to be on the cusp of being assigned - combines many of the original mutations from B.1.1.529 with those from BA.1, BA.2 and some new ones. Identified in UK and SA samples.

 

[_Russ_]

I suppose the sheer number of cases spurred on by Omicron will itself provide more and more chances of mutations.
It really seems like the Virus has the controlling hand.

 

[existentialist]

I suppose the sheer number of cases spurred on by Omicron will itself provide more and more chances of mutations.
It really seems like the Virus has the controlling hand.

Yep. By its nature, the virus mutates, and all we can do is play catch-up. We repeatedly squander every opportunity we might have to plan ahead (which the virus can't do), and restrict transmission, but that aside, Mister Covid is definitely in charge here.

 

[Pickman's model]

I suppose the sheer number of cases spurred on by Omicron will itself provide more and more chances of mutations.
It really seems like the Virus has the controlling hand.

yeh. who do you think is smarter, the virus or alexander boris de pfeffel johnson?

 

[prunus]

yeh. who do you think is smarter, the virus or alexander boris de pfeffel johnson?

Well one's an unthinking parasite on humanity sowing chaos and disaster wherever it goes, and the other...

 

[elbows]

I still preferred the approach where countries tried to minimise number of infections at all times. I know a lot of people cheered on the end of 'zero covid' approaches in a handful of countries that went for that approach but I think they were wrong to do so. I expect I will revisit this theme plenty in future if we have ongoing massive problems. However I'd still much rather things calmed down on the pandemic front and did not leave me with as many reasons to rant and rave about that in future. So I'll try to give it a fair few months before evaluating whether I should make loud noises on this front again.

For now I'll just point out that these tweets passed across my radar the other day:

 

[2hats]

Separately, a new omicron sub-lineage, BA.3, appears to be on the cusp of being assigned - combines many of the original mutations from B.1.1.529 with those from BA.1, BA.2 and some new ones. Identified in UK and SA samples.

BA.3 now assigned. Key mutations in spike are:

A67V, HV69del, VYY143del, NL211I, G339D, S371F, S373P, S375F, D405N, K417N, N440K, G446S, S477N, T478K, E484A, Q493R, Q498R, N501Y, Y505H, D614G, H655Y, N679K, P681H, N764K, D796Y, Q954H, N969K

 

[2hats]

(UWash and many others) A study of both neutralising antibodies to omicron/B.1.1.529 (VSV pseudovirus assay) and antigenic shift of that variant.

Amongst various results they reproduce loss of neutralisation by a number of approved vaccines (original approved dosing regimens), including first glimpses of Sputnik V and Sinopharm BBIBP-CorV.

They also note that broadly neutralising sarbecovirus antibodies, which recognise four conserved antigenic sites in the RBD, retain activity against omicron/B.1.1.529. In particular S2K146 which mimics hACE2.

In addition, they observed how omicron/B.1.1.529 RBD not only binds with increased affinity to human ACE2, but unlike some recent VOC, has gained binding to murine ACE2 (likely due to Q493R).

The magnitude of Omicron-mediated immune evasion and the acquisition of binding to mouse ACE2 mark a major SARS-CoV-2 mutational shift [...] we and others propose that the Omicron shift may result from extensive viral replication in immunodeficient hosts or from inter-species ping-pong transmission between humans and rodents, as previously described for minks.

DOI: 10.1101/2021.12.12.472269.

 

[2hats]

And, a preprint of a study from the Chinese Academy of Sciences...

The molecular spectrum (i.e., the relative frequency of the twelve types of base substitutions) of mutations acquired by the progenitor of Omicron was significantly different from the spectrum for viruses that evolved in human patients, but was highly consistent with spectra associated with evolution in a mouse cellular environment. Furthermore, mutations in the Omicron spike protein significantly overlapped with SARS-CoV-2 mutations known to promote adaptation to mouse hosts, particularly through enhanced spike protein binding affinity for the mouse cell entry receptor. Collectively, our results suggest that the progenitor of Omicron jumped from humans to mice, rapidly accumulated mutations conducive to infecting that host, then jumped back into humans, indicating an inter-species evolutionary trajectory for the Omicron outbreak.

DOI: 10.1101/2021.12.14.472632.

 

[elbows]

"an escaped mutant" is the technical term?? (per whitty on the telly) they could find a more reassuring phrasing, no?

Note that the use of the term variants caught on and authorities and others mostly stopped using the phrase 'escape mutant' in public. Had the term received more widespread ongoing use, based on what we know so far Omicron would have qualified.

 

[2hats]

Preliminary variant T cell study from LJI (Sette). Initial analysis of the entire SARS-CoV-2 proteome indicates 88% of CD4+ and 95% of CD8+ T cell epitopes are conserved in omicron/B.1.1.529.

(NIH/ImmunoScape) Preprint indicating further confirmation of conservation of T cell epitopes across variants, including omicron/B.1.1.529.
Only one known T cell epitope was identified as having mutated and possibly 'escaped' from T cell responses seen in convalescent patients. This represented a very small (<1%) fraction of CD8+ T cell responses seen in those individuals (132 separate CD8+ T cell responses, targeting 52 unique epitopes, were seen in their study partici
pants).

These data suggest that virtually all individuals with existing anti-SARS-CoV-2 CD8+ T-cell responses should recognize the Omicron VOC, and that SARS-CoV-2 has not evolved extensive T-cell escape mutations at this time.

Bear in mind that this is based on a small sample and did not investigate vaccine induced T cell responses (which may be broader, or indeed narrower).
DOI: 10.1101/2021.12.06.471446.

 

[2hats]

(China) A study of VOC transmissibility in mice, particularly interesting in the light of the research highlighted in posts #442 and #443 when one considers the prevalence of beta/B.1.351 in southern Africa for much of 2021.

This study reports direct contact transmission of the SARS-CoV-2 variant beta/B.1.351 in wild-type mice. They found that beta had acquired the ability to infect mice through enhancing the binding affinity of its RBD to mouse ACE2. A pseudovirus assay using both human and mouse ACE2 expressing target cells found that whilst delta/B.1.617.1 exhibited higher human ACE2 affinity than other VOCs tested (alpha/B.1.1.7, beta/B.1.351, gamma/P.1), beta/B.1.351 possessed higher affinity to mouse ACE2 than the others.


The authors speculate that variants with mutations similar to beta (eg such as gamma, seen here) may also be able to infect mice. This work suggests that some RBD mutations may be playing a role in extending the host range of the virus (they note the similarity of ACE2 receptors of wild mice and rats with those of the wild-type mice studied here). Though it is not yet clear whether the extension of host range and immune evasion is simply coincidence or co-evolution. Irrespective, these RBD mutations might be enriching opportunities for bi-directional anthroponosis/zoonosis, providing reservoirs for ongoing bursts of transmission (SARS-CoV-2 has now been detected in several different wild and domesticated species), and perhaps providing pointers to the origin of the original virus as well as some key variants.
DOI: 10.1038/s41392-021-00848-1.

 

[2hats]

A preprint of a predictive investigation (Leicester, Nottingham) using in vitro evolution to identify SARS-CoV-2 mutations that may increase transmissibility or immune evasion and determine mechanistic advantages of binding through cryo-em aided modelling.

They identify that the double mutation Q498H, or Q498R plus N501Y, can boost RBD affinity to ACE2, in particular in rats (early-type SARS-CoV-2 can not bind RaACE2). They determine that Q498 in particular is a pivotal position through which the virus can access large affinity gains and cross-species binding via one of two alternative mutational routes, determined by whether or not the variant possesses the N501Y mutation.

Notably Q498R plus N501Y is a feature of omicron/B.1.1.529 which has the potential to facilitate cross-species transmission. Obviously transmission of the virus to a species that is widespread and lives close to humans is of concern; variants with Q498H or Q498R plus N501Y have already been detected in wastewater. Further evolution in a synanthropic reservoir clearly carries a risk of spill back of novel variants to humans.
DOI: 10.1101/2021.12.23.473975.

 

[_Russ_]

Do we have to vaccinate Mice, deer, dogs etc?, absurd notion of course but this fucking bug seems to be out to get everything

 

[gentlegreen]

How will we know when we have "cracked" this thing ?

 

[Dogsauce]

Mice not that dissimilar from bats entomologically, am I right? So that sort of fits. If the rats can provide a reservoir for the disease then that’s London fucked.