Covid Mutations

[elbows]

 

[2hats]

See also post #1357 here.

 

[2hats]

New analysis of UK Sanger data suggesting delta has a growth advantage over alpha of about 70% (which may correspond to an effective R of around 1.7; though this depends on the generation time).

More details in this thread.

 

[2hats]

PHE SARS-CoV-2 variant data update, version 7, out today along with Technical Briefing 17.

Lambda C.37 (significant numbers across South America) has been added for monitoring (6 sequences seen in the UK since 23 Feb 2021). Notably this has L452Q in spike (along with G75V and T76I) and no P681H (cf B.1.1.7).

Also mentioned is delta-AY.2. This clade hasn't been seen in the UK yet but has been seen in the US (since 13 May 2021, 86 sequences out of 91 globally). Whilst AY.2 and AY.1 are very similar in spike, where there are commonalities with their parent lineage B.1.617.2, the major differences are in ORF1ab, some of which may, amongst other roles, play a part in modulating cell signalling and thereby facilitate some degree of immune evasion.

 

[elbows]

Ah I see that is technical priefing 17 but its numbered wrong in the link.

Due to my previous speculation about whether they would do an enhanced response for AY.1 cases, I note this bit:

Delta with K417N can be detected by genotyping assay, which means that rapid case identification and response activities can be undertaken. Until laboratory characterisation has been undertaken, Health Protection Teams will respond with high priority to case finding and control measures for cases of Delta with K417N. Neutralisation assays are now underway for Delta-AY.1

 

[2hats]

A mutation to monitor: P272L in the N-terminal domain of spike. More on the role/implications of this in the vaccine thread - see post #1376.

 

[2hats]

From Singapore, an analysis of viral loads and clinical features of VOCs alpha/B.1.1.7, beta/B.1.315 and delta/B.1.617.2 in some 800+ patients.

After adjusting for age and gender, delta was associated with higher odds of oxygen requirement, ICU admission, or death - an adjusted odds ratio (aOR) of 4.90, [95%CI: 1.43-30.78]. After adjusting for age, gender, comorbidities, and vaccination, aOR for pneumonia with delta was 1.88 [95%CI: 0.95-3.76] compared with wild-type. Notably, vaccine breakthrough cases were less severe.

Delta was associated with significantly lower PCR Ct values (thus higher viral load), significantly longer duration of Ct value ≤30 (estimated median duration of 18 days for delta versus 13 days for wild-type) and prolonged respiratory viral shedding. This may help explain why delta appears to be more contagious than previous types.

DOI: 10.2139/ssrn.3861566.

 

[2hats]

In vivo confirmation via several animal models that alpha/B.1.1.7 outcompetes beta/B.1.351, and the parental D614G variant. B.1.1.7 had a clear fitness advantage in upper respiratory tract replication and transmission dynamics (arising from three amino acid deletions and six substitutions in spike).

DOI: 10.1101/2021.06.28.450190.

 

[elbows]

I see that there is hardly anything other than Alpha and Delta showin up in the variant surveillance figures at the moment. eg no new Lambda cases added to the figures since they first listed that one, and only about 24 samples that werent Alpha or Delta.

Variants: distribution of case data, 9 July 2021

www.gov.uk

 

[elbows]

I see they have a risk assessment for Lambda now:

https://assets.publishing.service.gov.uk/government/uploads/system/uploads/attachment_data/file/1000662/8_July_2021_Risk_assessment_for_SARS-CoV-2_variant_LAMBDA_01.00-1.pdf

 

[elbows]

I havent read technical briefing 18 properly yet. But I note these thngs from the summary:

the number of genome sequence results available is maintained but the coverage has fallen with the increasing case numbers

secondary attack rates have fallen but remain higher for Delta than for Alpha. New data is included on the prevalence of mutations of predicted antigenic significance in the global dataset – there is an increase in mutations of predicted antigenic significance over time, even outside the designated variants of concern and variants under investigation

additional spike mutations are occurring on Delta but are present at relatively low frequencies both in the UK and global datasets

there is an increase in PCR positivity in the SIREN (national healthcare worker) cohort and a small but increasing number of possible reinfections

two new variants in monitoring have been designated (B.1.619 and B.1.629

 

[2hats]

two new variants in monitoring have been designated (B.1.619 and B.1.629

B.1.619: first recorded in Switzerland amongst returnees from Cameroon. Now seen in several European countries and the US. Mutations in membrane, nucleocapsid, ORF plus in spike: I210T, N440K, E484K, D614G, D936N, S939F, T1027I.

B.1.629: first spotted in Angola, now appearing in several European countries. Features mutations in ORF, non-structural proteins, membrane and nucleocapsid, plus in spike: G142D, K182R, L452R, T478K , D614G, D796Y.

Elsewhere, B.1.351.4 and A.30 have just been designated.

B.1.351.4, spotted in Botswana/SA, loses E484K, N501Y and the 241/243 deletion, but has gained L452R and T478K, which joins K417N.

A.30, seen in travellers from Tanzania/Angola, spotted in UK and Sweden. Features mutations in membrane, nucleocapsid, a lot of mutations in non-structural proteins, plus in spike: D80Y, D215G, E484K, H655Y, L249M, P681H, Q957H, R346K, T478R with deletions in 144, 210, 246-248.

 

[2hats]

From China/Oxford, an analysis of delta/B.1.617.2 infected quarantinees, which indicates that the viral replication rate of delta is higher, and the associated viral loads are typically around 1000 times greater, than those seen in early pandemic variant (19A/19B) infections. This highlights the more infectious nature of delta during the early, asymptomatic stage.

 

[2hats]

B.1.351.4, spotted in Botswana/SA, loses E484K, N501Y and the 241/243 deletion, but has gained L452R and T478K, which joins K417N.

Now withdrawn - appears to be a contamination issue (beta with delta).

 

[elbows]

 

[elbows]

Some quotes from that paper since these are both areas of repeated interest to me.

Compromise of bamlanivimab, but not imedevimab, was previously noted for B.1.617.1 and B.1.617.24,48. The REGN-COV2 dual monoclonal antibody therapy containing casirivimab and imedevimab was shown to improve survival, and our data showing reduced efficacy for imedevimab against B.1.617.2 might compromise clinical efficacy. Moreover, it could lead to possible selection of escape variants where there is immune compromise and chronic SARS-CoV-2 infection with B.1.617.2. Further work to explore these possibilities is urgently needed.

Although weaker protection against infection with B.1.351 (Beta) (the variant with least sensitivity to neutralising antibodies) has been demonstrated for at least three vaccines, progression to severe disease and death has been low. Therefore, at population scale, extensive vaccination will likely protect against moderate to severe disease due to B.1.617.2. Indeed, data from the UK already demonstrate low incidence of severe disease in vaccinees (PHE technical report 17). However, our data on ChAdOx-1 vaccine breakthrough and reduced vaccine efficacy against symptomatic B.1.617.2 infection are of concern given that hospitals frequently treat individuals who may have suboptimal immune responses to vaccination due to comorbidity. Such patients could be at risk for severe disease following infection from HCW or other staff within hospital environments. Transmissions in vaccinated HCW could potentially involve overdispersion or super-spreading, and indeed we document such an event in one of three hospitals studied. Therefore strategies to boost vaccine responses against variants are warranted in HCW and attention to infection control procedures should be continued even in the post vaccine era.

 

[Supine]

KLAXON ALERT

New Covid variant under investigation in the UK, PHE says

No evidence to suggest it causes more severe illness, PHE says

www.independent.co.uk

Not sure if this one is new new or seen elsewhere already.

 

[elbows]

KLAXON ALERT

New Covid variant under investigation in the UK, PHE says

No evidence to suggest it causes more severe illness, PHE says

www.independent.co.uk

Not sure if this one is new new or seen elsewhere already.

Page 51 & 52 of https://assets.publishing.service.g...t_data/file/1005517/Technical_Briefing_19.pdf

I'm not quoting everything it says about it, eg I've left out the mutation details and the vaccination status of UK cases.

VUI-21JUL-01 was identified through international variant horizon scanning and was made a signal in monitoring by PHE on 7 June 2021 (lineage B.1.621 at the time). On 20 July 2021, PHE designated lineage B.1.621 as a new variant of interest, VUI-21JUL-01, based on apparent spread into multiple countries, importation to the UK and mutations of concern.

As of 20 July 2021, 1,230 sequences on GISAID have been assigned to the B.1.621 lineage. B.1.621 sequences have been uploaded from Colombia (325), US (264), Spain (196), Mexico (122), Netherlands (65), Aruba (57), Ecuador (56), Italy (47), Portugal (19) United Kingdom (16), Switzerland (13), Curacao (12), Costa Rica (5), Denmark (5),Germany (5) Bonaire (4), Belgium (3), France (3), Brazil (2), Hong Kong (2), Japan (2), Poland (2), Slovakia (2), Austria (1), Ireland (1), and Sint Maarten (1). Figure 19 shows the distribution of case per country over time, based on GISAID data, indicating that an increasing number of countries reported cases in June and July.

As of 22 July 2021, there are 16 cases of VUI-21JUL-01 in England plus an additional 6 genomes for which case data is being sought. Cases have been detected in 3 different regions in England, with the majority of cases detected in London (10, 63%). The 20-to-29 years age group formed the largest age group (6 cases). Three of the 16 cases have history of travel which include travel from or transit through Mexico, Spain, Dominican Republic and Colombia.

 

[elbows]

More on that variant from the latest technical briefing:

1.8.1 Genotype to Phenotype (G2P) Consortium
Preliminary pseudovirus neutralisation data indicates that:

• sera from vaccinees shows decreased ability to neutralize B.1.621 compared to first wave virus and Alpha, with a magnitude of change similar to Beta
• sera from individuals who have been infected with Delta does not have strong neutralising activity against either Beta or B.1.621
• sera from individuals who have been vaccinated and have had subsequent recent Delta infection have a high level of neutralising activity against all variants tested (including beta and B.1.621)

https://assets.publishing.service.gov.uk/government/uploads/system/uploads/attachment_data/file/1009243/Technical_Briefing_20.pdf

Also sadly as expected the percentage of samples being sequenced plunged horribly due to the sheer number of positive cases in this wave. Same story as the last wave, inevitable and reduces our ability to survey the variant situation at all properly.


In terms of the major variants that went on to become dominant so far, we were lucky that whether there was s-gene dropout or not was the opposite each time, offering an easy way to track the decline of one variant and the new one rising without needing to sequence. We cant rely on that being the case every time.

 

[elbows]

This thread from someone at PHE is a useful cummary of various things in the technical report and risk assessment. Includes stuff about no reduction of viral load in vaccinated versus vaccinated that I've mentioned on the vaccine thread today.

 

[elbows]

And one of the many things that thread covers is how genomic sequencing is being prioritised at a time when it cannot hope to sequence a high proportion of cases.

 

[2hats]

An investigation of potential mutations leading to convalescent and vaccine immunity escape (Rockefeller).

By combining substitutions, both targeted by polyclonal plasma antibody and seen in various VOC, into a single polymutant spike protein, they show that 20 naturally occurring mutations in SARS-CoV-2 spike are sufficient in combination to confer almost complete resistance to neutralising antibodies elicited by both convalescents and non-convalescent mRNA vaccine recipients.

Notably, sera from previously infected individuals who had received mRNA vaccination, neutralised this SARS-CoV-2 polymutant, as well as neutralising a diverse range of sarbecoviruses. Likely this arose from extensive affinity maturation following the availability of numerous epitope targets.

This suggests immunity, possessing suitable breadth and affinity, is both achievable and should be resilient to a range of future, as yet unseen, SARS-CoV-2 variants, and indeed might confer degrees of protection against future sarbecovirus pandemics. Furthermore, it may indicate that a suitable dosing interval with a booster, perhaps even ideally heterologous, may be advantageous moving forward.
DOI: 10.1101/2021.08.06.455491.

 

[2hats]

From Israel, an evolutionary analysis of variants, focussed primarily on delta/B.1.617.2 and a comparison with alpha/B.1.1.7.

The authors note that delta is composed of several distinct clades (which the authors name A-E). In particular, clade D, characterised by several non-synonymous mutations in non-structural proteins and notably T140I in ORF7b plus G215C in nucleocapsid, has come to dominate many global regions, though there is (for example) no apparent statistically significant difference observed in cycle thresholds between D and A, B, C, E.

It is not yet clear as to whether selection or random genetic drift has afforded this advantage.

DOI: 10.1101/2021.08.05.21261642.

 

[2hats]

This suggests immunity, possessing suitable breadth and affinity, is both achievable and should be resilient to a range of future, as yet unseen, SARS-CoV-2 variants, and indeed might confer degrees of protection against future sarbecovirus pandemics. Furthermore, it may indicate that a suitable dosing interval with a booster, perhaps even ideally heterologous, may be advantageous moving forward.
DOI: 10.1101/2021.08.06.455491.

Related, a detailed study (5 participants, Rockefeller) of the properties of SARS-CoV-2 neutralising antibodies that change as a consequence of accumulated somatic mutations over many months in convalescent individuals.

Longitudinal maturation was observed to increase the potency of SARS-CoV-2 neutralising antibodies, restricting options for viral escape, with antibody-spike structures revealing evolutionary changes that improved potency and breadth. Additionally, as above, some antibodies enabled neutralisation of additional sarbecoviruses.

SARS-CoV-2 viral proteins and nucleic acids persist in the gastrointestinal tract of convalescents for several months providing a source of antigen to fuel germinal centres. It is not yet clear as to whether current vaccination regimens will provide similar. This work suggests that immunisation schemes that elicit higher levels of antibody mutation and diversification are desirable.
DOI: 10.1016/j.immuni.2021.07.008.

 

[teuchter]

An investigation of potential mutations leading to convalescent and vaccine immunity escape (Rockefeller).

By combining substitutions, both targeted by polyclonal plasma antibody and seen in various VOC, into a single polymutant spike protein, they show that 20 naturally occurring mutations in SARS-CoV-2 spike are sufficient in combination to confer almost complete resistance to neutralising antibodies elicited by both convalescents and non-convalescent mRNA vaccine recipients.

Notably, sera from previously infected individuals who had received mRNA vaccination, neutralised this SARS-CoV-2 polymutant, as well as neutralising a diverse range of sarbecoviruses. Likely this arose from extensive affinity maturation following the availability of numerous epitope targets.
View attachment 283041
This suggests immunity, possessing suitable breadth and affinity, is both achievable and should be resilient to a range of future, as yet unseen, SARS-CoV-2 variants, and indeed might confer degrees of protection against future sarbecovirus pandemics. Furthermore, it may indicate that a suitable dosing interval with a booster, perhaps even ideally heterologous, may be advantageous moving forward.
DOI: 10.1101/2021.08.06.455491.

Is it possible to have a lay-persons brief explanation of what this all means?

 

[2hats]

Is it possible to have a lay-persons brief explanation of what this all means?

Given sufficient time and breadth of training, with repeated exposures to a range of antigens, the human immune system can develop the potential to neutralise future SARS-CoV-2 variants and also related viruses. Some of this is likely at the root of various observations of cross-reactivity leading to memory immune responses and aborted infections in a small number of non-convalescents.

Convalescent vaccinees often demonstrate an advantage over those not previously infected (perhaps influenced by one or more of: route of antigen delivery - URT versus intramuscular; antigen nature - intact virus versus spike only; antigen persistence - weeks or even months versus hours to days). Another recent preprint, again from Rockefeller, investigating post-vaccination antibody evolution, produced results which suggested that boosting vaccinated non-convalescents with current mRNA vaccines would produce a quantitative increase in plasma neutralising activity (boost antibodies) but not yield the qualitative advantage against variants observed after vaccinating convalescent individuals (breadth, potency and affinity of memory responses).
DOI: 10.1101/2021.07.29.454333.

These results could help inform optimisation of future vaccination designs and schedules.

 

[elbows]

I havent looked into the following properly at all yet:

 

[Badgers]

Yeah

I stuck that in the world thread just now. Not got your knowledge on such matters sir.

 

[elbows]

I note the AY.3 version of Delta is mentioned in this small study of a particular hospital outbreak.

Cryptic Transmission of the Delta Variant AY.3 Sublineage of SARS-CoV-2 among Fully Vaccinated Patients on an Inpatient Ward

Background Recent reports indicate that vaccination is effective in reducing symptomatic infection with the Delta variant of SARS-CoV-2 (DV) but is less protective against asymptomatic transmission of DV in outpatients than for earlier variants. Here we report cryptic transmission associated...

www.medrxiv.org

Our findings support a growing literature that vaccination does not prevent the development of high viral load in the nasopharynx of persons infected with the Delta variant or the propensity for asymptomatic transmission,10,11 in contrast to findings with earlier variants.6-9 Brown et. al. 11 recently described community transmission of the Delta variant B.1.617.2 in a cohort of predominantly vaccinated persons who congregated unmasked in indoor spaces. High viral load did not differ between vaccinated and unvaccinated persons. In that study, sequencing identified the Delta variant (B.1.617.2) in 89% of cases and the Delta AY.3 sublineage in just 1%. In the current study, sequencing identified the Delta AY.3 sublineage 4 of 4 cases. Our observations indicate that transmission of the Delta variant sub-lineage AY.3 may occur among vaccinated persons even in the more controlled environment of an inpatient medical-surgical ward. It remains to be determined whether the Delta variant AY.3 lineage is more transmissible than the Delta Variant B.1.617.2. Our findings do raise concern that without stricter risk mitigation, nosocomial transmission of the Delta variant and Delta sublineages will occur more frequently than with prior, less transmissible variants, even in vaccinated persons.

 

[elbows]

Yeah

I stuck that in the world thread just now. Not got your knowledge on such matters sir.

Well what tends to happen with variant news is that it remains somewhat vague and geeky until a new strain takes hold and demonstrates a trajectory where it looks set to dominate. Then its much easier to talk about and for people to understand the implications. But unless that stage is reached, I wouldnt really know what to tell people in terms of paying attention and showing concern towards a new strain. And there have obviously been quite a lot of strains that havent dominated, and if I spoke with too much concern about every one of those then I'd be a never-ending stream of bad news without enough certainty. At this moment AY.3 sounds like one to keep an eye on, but I wont run far with it because its not clear whether it will end up with an advantage that allows it to dominate.