Covid Mutations

[elbows]

I may as well quote from the September 9th UK variants government document:

Newly designated variant – V-22SEP-01 (BA.4.6)

Omicron sub-lineage BA.4.6 was identified as part of horizon scanning on 15 August 2022. On 1 September 2022 BA.4.6 was designated as variant V-22SEP-01.

BA.4.6 has a mutation in a known antigenically significant site (S: R346T) and an apparent small growth advantage relative to BA.5. BA.4.6 represented 3.31% of UK samples for the week beginning 14 August 2022.

The University of Oxford reported preliminary neutralisation data to the Variant Technical Group. Pseudoviral neutralisation assays performed on BA.4.6 show that titres are reduced 2-fold, compared to neutralisation of BA.4 or BA.5 using sera from triple dosed recipients of the Pfizer BNT162b2 vaccine.

V-22JUL-01 (BA.2.75)

As of 6 September 2022, there were 100 cases with BA.2.75 in the UK. Of these, 89 were in England, 7 in Scotland and 4 in Wales. BA.2.75 is currently increasing in frequency in England. The growth rate increased from July 2022 to August 2022 and is currently 61% per week compared to co-circulating lineages.

Two sub-lineages of BA.2.75 (BA.2.75.1 and BA.2.75.2) are currently being assessed. Sub- lineage BA.2.75.1 is defined by the addition of S: D574V, and sub-lineage BA.2.75.2 by the addition of S:R346T, S:F486S, S: D1199N. Sub-lineage BA.2.75.2 was first identified as part of horizon scanning on 20 August 2022 and was made a signal in monitoring on 7 September 2022.

https://assets.publishing.service.gov.uk/government/uploads/system/uploads/attachment_data/file/1103869/Technical-Briefing-45-9September2022.pdf

 

[elbows]

I'm not going to pretend that I am clued up about this angle yet:

 

[2hats]

There seems to be a growing consensus on a pattern of evolutionary convergence for recent omicron sub-lineage RBD mutations, focused on
R346T, K444T and N460K in spike. In particular, BQ.1.1 appears to be emerging as one of the front runners (particularly perhaps in the UK), alongside BA.2.75.2, BJ.1, BA.2.10.4 and BA.2.3.20.

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(PekingU) Possibly we are seeing viral mutational evolution searching around a local maxima for optimal configuration in RBD in the face of current prevailing population immunity and thus escape from BA.5 infection/booster. (Or 'stuck' in a saddle, if you like, a fight constrained by immunity evasion versus arrangements advantageous to other viral attributes/stages eg fusion, replication, etc).
DOI:10.1101/2022.09.15.507787v2
Overview thread:

Yunlong Richard Cao (@yunlong_cao)

Updating information regarding convergent variants BA.2.3.20, BN.1, BA.2.10.4, BN.2.1, BA.4.6.1, BQ.1, BQ.1.1. In short, BA.2.75.2 and BQ.1.1 are the most antibody-evasive convergent variants tested, far exceeding BA.5 and approaching SARS-CoV-1 level. (1/4)

nitter.it

(Scripps/Fred Hutch/MIT/UWash/others) However, and perhaps not entirely unsurprisingly (for those paying attention this far), given adequate time for affinity maturation (≳6 months) neutralisation titres are improved, largely restored, by heterologous exposures to antigen, with little impact from Original Antigenic Sin (here subjects originally vaccinated with original WT-based mRNA-1273 subsequently then infected with omicron BA.1).

​

DOI:10.1101/2022.09.21.508922
Overview thread:

Bloom Lab (@jbloom_lab)

This study on response to Omicron after #SARSCoV2 vaccination provides some optimism re “original antigenic sin” https://www.biorxiv.org/content/10.1101/2022.09.21.508922v1 TLDR: although response to Omicron dominated by preexisting B-cells, antibodies from these cells better at 6 months than 1...

nitter.it

 

[_Russ_]

There seems to be a growing consensus on a pattern of evolutionary convergence for recent omicron sub-lineage RBD mutations, focused on
R346T, K444T and N460K in spike. In particular, BQ.1.1 appears to be emerging as one of the front runners (particularly perhaps in the UK), alongside BA.2.75.2, BJ.1, BA.2.10.4 and BA.2.3.20.

View attachment 344239 View attachment 344243​

View attachment 344244​

(PekingU) Possibly we are seeing viral mutational evolution searching around a local maxima for optimal configuration in RBD in the face of current prevailing population immunity and thus escape from BA.5 infection/booster. (Or 'stuck' in a saddle, if you like, a fight constrained by immunity evasion versus arrangements advantageous to other viral attributes/stages eg fusion, replication, etc).
DOI:10.1101/2022.09.15.507787v2
Overview thread:

Yunlong Richard Cao (@yunlong_cao)

Updating information regarding convergent variants BA.2.3.20, BN.1, BA.2.10.4, BN.2.1, BA.4.6.1, BQ.1, BQ.1.1. In short, BA.2.75.2 and BQ.1.1 are the most antibody-evasive convergent variants tested, far exceeding BA.5 and approaching SARS-CoV-1 level. (1/4)

nitter.it

(Scripps/Fred Hutch/MIT/UWash/others) However, and perhaps not entirely unsurprisingly (for those paying attention this far), given adequate time for affinity maturation (≳6 months) neutralisation titres are improved, largely restored, by heterologous exposures to antigen, with little impact from Original Antigenic Sin (here subjects originally vaccinated with original WT-based mRNA-1273 subsequently then infected with omicron BA.1).

View attachment 344241​

DOI:10.1101/2022.09.21.508922
Overview thread:

Bloom Lab (@jbloom_lab)

This study on response to Omicron after #SARSCoV2 vaccination provides some optimism re “original antigenic sin” https://www.biorxiv.org/content/10.1101/2022.09.21.508922v1 TLDR: although response to Omicron dominated by preexisting B-cells, antibodies from these cells better at 6 months than 1...

nitter.it

Im lost, are you saying something like, the virus is poking around with a stick to find a weak spots it can reach without evolving too much rather than sending out scouts to see whats further out that might take a bit more effort to breach?

 

[elbows]

The complex mess of variants have been hard for me to get a handle on but thanks to the most recent indie SAGE video tipping me off about a particular twitter source of visuals, there is this where he has grouped various upcoming strains together to make them show up more clearly (eg the ones grouped together as pink):

 

[elbows]

Also stuff from them such as:

 

[elbows]

BQ.1 and BQ.1.1 continued to do their thing. I havent been paying very much attention so am behind with this.



Edit - here is a later version:

 

[elbows]

I hadnt seen this sort of info in such a handy chart form before:

 

[Aladdin]

I hadnt seen this sort of info in such a handy chart form before:

Does this mean the boosters wont protect against B.Q. 1.1 ?

Or is it about the treatment not working?

 

[2hats]

Not in the immunocompetent. It's just illustrating degrees of escape from specific monoclonal antibody treatments.

 

[elbows]

Indeed. For example:

Our data reveal that emerging omicron sublineages are resistant to most (ie, BA.4.6, BA.2.75.2, and BJ.1) or all (BQ.1.1) clinically used mAbs. As a consequence, in patients at high risk, treatment with mAbs alone might not provide a therapeutic benefit in regions of the globe in which BQ.1.1 is spreading, suggesting that additional treatment options (eg, paxlovid or molnupiravir) should be considered. Furthermore, novel, broadly active mAbs are urgently needed for prophylactic or therapeutic treatment, or both, in patients at high risk.

Omicron sublineage BQ.1.1 resistance to monoclonal antibodies

Vaccination represents the key strategy to control the COVID-19 pandemic through induction of neutralising antibody responses and T cell-associated immunity that substantially decrease the risk of developing severe disease.1,2 However, individuals who are immunocompromised (eg, because of...

www.thelancet.com

So we end up with articles like this one:

archive.ph

In the evolutionary chess match between the coronavirus and humans, scientists’ next move can’t come soon enough for the millions of Americans relying on treatments known as monoclonal antibodies. These lab-made therapies are rapidly losing their healing power, forcing researchers around the world to devise new antibodies that are both more potent and more resistant to new variants.

“I would say it’s a big problem,” said Michael Barnett, associate professor of health policy and management at Harvard University’s T.H. Chan School of Public Health.

People with weakened immune systems represent about 3 percent of all Americans and 12 percent of U.S. patients hospitalized with covid-19. Moreover, one of the most effective alternative treatments remaining, Paxlovid, has interactions with other drugs that would make it too risky for use by people with compromised immune systems, especially organ transplant patients.

Driven by this urgent need, scientists are exploring new ways to tackle the problem — including antibodies that seek out fresh targets among the vulnerable parts of the virus.

“I would hope that some of these will be in clinical trials soon, and then it won’t take long” to determine whether they work, said William Haseltine, a former Harvard Medical School professor who founded the university’s cancer and HIV/AIDS research departments.

“Either it protects you from infection, or it doesn’t.”

One new antibody cocktail developed by the Sherbrooke, Quebec, biotechnology company Immune Biosolutions is in clinical trials in South Africa and Brazil. Participants receive the treatment as a mist sprayed into their mouths for about three minutes while they breathe normally.

 

[2hats]

Mutation news...

Concerns about the mutagenic potential of some antivirals were raised a year ago but evidence may be stacking up against molnupiravir:

Ryan Hisner (@LongDesertTrain)

Approval for molnupiravir (MOV) use should be revoked worldwide. Not only has it proven ineffective, it seems clearly to be creating sequences such as the one below, which in ~2 months acquired 72 mutations, more than its lineage had accumulated in ~3 years of evolution. 1/

nitter.hu

Separately, a fairly thorough and extensive analysis of the recent evolution of SARS-CoV-2 variants in the omicron era, including simple and complex recombinants and convergent evolution:

SARS-CoV-2 evolution, post-Omicron

SARS-CoV-2 evolution, post-Omicron Cornelius Roemer1, Ryan Hisner2, Nicholas Frohberg2, Hitoshi Sakaguchi3, Federico Gueli4, Thomas P. Peacock5 1Biozentrum, University of Basel, Basel, Switzerland; Swiss Institute of Bioinformatics 2Independent Researcher, USA 3Retired, Japan 4Independent...

virological.org

The conclusions of which may not be entirely unconnected to patterns of antiviral use as well as chronic infections…

it is entirely possible all the lineages described here would be outcompeted in the event of a second ‘Omicron-like event’ – the emergence of a brand new variant with orthogonal antigenicity from any other circulating lineages, for example from an ancestral or pre-Omicron variant genetic background. Due to its singular nature, it is extremely unclear how likely or how commonly we should expect such events going forwards, however it seems prudent to have strategies in place in the event this were to occur.

Emergence of a saltation variant from a Delta genetic background is of particular concern, although it’s entirely possible the intrinsically higher pathogenicity of Delta might well have changed upon re-emergence. It should be noted that a number of Delta sequences continue to be sampled, most with large numbers of private mutations suggesting there is an existing, potentially substantial, reservoir of Delta (as well as prior variants). Such sequences most likely represent ongoing chronic infections, as exemplified by the emergence of the complex recombinants.

 

[elbows]

I never saw this paper in the first place but now it has been obliterated anyway:

A paper published earlier this month by Science claiming the Omicron variant of SARS-CoV-2 arose gradually, across a broad area of Africa, before it was detected was retracted today by its authors. In a retraction notice, all 87 researchers involved in the paper acknowledged that crucial genome sequences on which the study based its conclusions were a result of contamination. “We made a mistake and that is bitter,” says senior author Felix Drexler of Charité University Hospital in Berlin.

Science | AAAS

www.science.org

 

[elbows]

XBB.1.5 has appeared in the news recently due to the rise in proportion of cases caused by this variant in countries like the USA.

Reporting has featured the usual mix of alarm and reassurance. I will indulge in the usual waiting game to see what impact it has.

It appears that some people have decided to nickname it Kraken.

 

[elbows]

The original XBB was an opportunity for the concept of recombination to become more mainstream, eg see this explainer from a while back.

 

[elbows]

A BBC article about XBB.1.5

What is known about new Covid variant XBB.1.5?

The latest Omicron variant is making scientists take notice in the US - so what do you need to know?

www.bbc.co.uk

 

[CNT36]

Mutation news...

Concerns about the mutagenic potential of some antivirals were raised a year ago but evidence may be stacking up against molnupiravir:

Ryan Hisner (@LongDesertTrain)

Approval for molnupiravir (MOV) use should be revoked worldwide. Not only has it proven ineffective, it seems clearly to be creating sequences such as the one below, which in ~2 months acquired 72 mutations, more than its lineage had accumulated in ~3 years of evolution. 1/

nitter.hu

Separately, a fairly thorough and extensive analysis of the recent evolution of SARS-CoV-2 variants in the omicron era, including simple and complex recombinants and convergent evolution:

SARS-CoV-2 evolution, post-Omicron

SARS-CoV-2 evolution, post-Omicron Cornelius Roemer1, Ryan Hisner2, Nicholas Frohberg2, Hitoshi Sakaguchi3, Federico Gueli4, Thomas P. Peacock5 1Biozentrum, University of Basel, Basel, Switzerland; Swiss Institute of Bioinformatics 2Independent Researcher, USA 3Retired, Japan 4Independent...

virological.org

The conclusions of which may not be entirely unconnected to patterns of antiviral use as well as chronic infections…

More on Molnupiravir here.

Molnupiravir was developed by the pharmaceutical giant Merck, based in Rahway, New Jersey, and was authorized by regulators in the United States and United Kingdom in late 2021, and in Australia in early 2022. A company-sponsored clinical trial found that the drug — a pill taken for five days — reduced hospitalizations and deaths in people at risk of severe COVID-19.

Molnupiravir mimics some of the building blocks of RNA, the genetic material in SARS-CoV-2. The drug peppers the viral genome with mutations, which add up to make SARS-CoV-2 worse at replicating. This results in a marked reduction in SARS-CoV-2 levels in infected human cells and hamsters2.

But scientists have raised the possibility that, in rare cases, molnupiravir treatment might not entirely eliminate SARS-CoV-2, allowing some individuals who have taken the drug to continue to transmit the virus.

Merck are obviously still denying there is a problem suggesting that there is little evidence and those with variants will tell tale sequences may not even have taken the drug. Given evidence for transmission I'm not sure that is much of a defence.

 

[elbows]

Latest technical report from February 10th includes CH.1.1. Some relevant quotes from this document:

https://assets.publishing.service.gov.uk/government/uploads/system/uploads/attachment_data/file/1135877/variant-technical-briefing-50-10-february-2023.pdf

From UK sequences collected from 23 January 2023 to 30 January 2023, 37.5% were classified as V-22OCT-01 (BQ.1), 28.3% V-22DEC-01 (CH.1.1), 15.3% V-23JAN-01 (XBB.1.5), 5.5% V- 22JUL-01 (BA.2.75), 4.4% VOC-22APR-04 (BA.5), 3.4% V-22OCT-02 (XBB), 1.9% VOC- 22JAN-01 (BA.2) and 0.3% V-22SEP-01 (BA.4.6). The remaining sequences were classed as other, or of insufficient quality to assign.

Since the last technical briefing there are 4 additional signals in monitoring.

CH.1.1.1 and CH.1.1.2 are sub-lineages of the V-22DEC-01 variant which are increasing in proportional abundance, but currently do not have concerning additional mutations relative to the parent lineage.

XBF is a recombinant lineage that shares the mutation F486P found in XBB.1.5. This lineage has been observed in the UK at low proportions. In Australia, this lineage represents more than 15% of recent sequences uploaded to GISAID.

BQ.1.1.20 was flagged due to growth in Denmark, however in recent weeks this appears to be declining.

CH.1.1 and XBB.1.5 are the most competitive of the signals in monitoring or designated variants, across all models.

Preliminary analysis of the risk of hospital admission following presentation to emergency care indicates there is no increase in risk for people with CH.1.1 (V-22DEC-01) compared to BQ.1 (V-22OCT-01) (odds ratio: 1.03, 95% confidence interval 0.84 to 1.26). This analysis was adjusted for age, vaccination status, sex, reinfection status, deprivation, region and specimen test week. Results may change as further data becomes available.

The number of hospitalised cases with complete data is currently too small to be able to assess the severity of XBB.1.5.

A preliminary analysis has been undertaken comparing vaccine effectiveness (VE) against hospitalisation for CH.1.1 and BQ.1 as compared to BA.5. Although the effectiveness point estimates are lower for CH.1.1 and BQ.1 the confidence intervals are wide and overlap the estimate for BA.5. Currently the numbers of cases in the analysis are too small to confidently assess differences in VE between CH.1.1, BQ.1 and BA.5.

 

[elbows]

Also this quote from the same report, a quote I just mentioned this one in the main UK thread:

An increase in infection hospitalisation risk was observed over the summer of 2022; however, the most recent estimates have shown signs of a plateau. The latest estimate will not yet reflect any changes in severity from the recent growth in XBB.1.5.

I would suggest that the picture described there in terms of hospitalisation risk from summer 2022 onwards is consistent with what 2hats said on this thread back in June, before this change was estimated via real UK data, offering an explanation:

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.

I miss your updates about this side of things 2hats , they are very useful.

 

[elbows]

More on Molnupiravir here.

Merck are obviously still denying there is a problem suggesting that there is little evidence and those with variants will tell tale sequences may not even have taken the drug. Given evidence for transmission I'm not sure that is much of a defence.

The UK technical report on variants that I've just been quoting makes mention of it, and takes the typical 'do more UK analysis using existing UK methods' line:

Molnupiravir acts by introducing mutations into the viral genome to impair viral replication. The specific mechanism results in a typical mutational profile. The Francis Crick Institute reported analysis showing the presence of variants with this profile in countries which have deployed molnupiravir (Sanderson and others, 2023). The Variant Technical Group recommended that there should be further investigation of the effect of molnupiravir on viral genetic diversity, to understand the risks to the individual and public health. This should particularly include chronic infections including those in immunocompromised patients and should use existing surveillance and UK clinical trial data sets.

 

[elbows]

The BBC are rather out of date when they say this arent they? Or have I got confused in recent months?

Since last summer, different versions of the Omicron variant of Covid have been spreading the most - the latest being Omicron BQ.1.

From Covid booster jab to be offered this spring

 

[2hats]

The BBC are rather out of date when they say this arent they? Or have I got confused in recent months?



From Covid booster jab to be offered this spring

XBB family recombinants (descendants of BA.2.10.x and BA.2.75.x) are where it is at right now.

BQ.1 (BA.5.x) flavoured variants have been on the wane since the end of last year.

 

[elbows]

Latest UKHSA technical briefing has a focus on BA.2.86:

SARS-CoV-2 variant surveillance and assessment: technical briefing 53

www.gov.uk

Leading to press coverage such as:

New Covid variant BA.2.86 behind Norfolk care home outbreak

Health officials say it is too early to know whether BA.2.86 is more serious than previous strains.

www.bbc.co.uk

 

[2hats]

Mutation news...

Concerns about the mutagenic potential of some antivirals were raised a year ago but evidence may be stacking up against molnupiravir:

Clear evidence that molnupiravir creates genetically divergent SARS-CoV-2 variants that have replicated and been transmitted.

Antiviral drug linked to SARS-CoV-2 mutations

Researchers at the Francis Crick Institute, the University of Cambridge, Imperial College London, the University of Liverpool, the University of Cape Town and UKHSA have uncovered a link between an antiviral drug for COVID-19 infections called molnupiravir and a pattern of mutations in the...

www.crick.ac.uk

DOI:10.1038/s41586-023-06649-6.