Covid Mutations

[Aladdin]

At least they didnt mess around with obfuscating this bit:

What does this mean...in layman's English...for an immunocompromised person?

 

[elbows]

What does this mean...in layman's English...for an immunocompromised person?

In the case of that mutation they were talking about how this mutation was seen popping up in variations of the virus that they had found in immunocompromised patients, probably during a lengthy infection, quite possibly when attempts to help the patient included plasma from recovered patients.

So them mentioning it is in connection with the risk of that sort of mutation appearing in such patients, about how such mutations pop up in the first place. And the implications of a strain with such mutations taking hold that can escape peoples immunity more broadly.

Its not being mentioned in the context of some additional implications and risks specific to people with compromised immune systems should they catch a version of the virus that takes off in the wild and carries that particular mutations, if thats why you were asking.

Sorry if this explanation is still a bit wordy. I can try again if necessary, let me know.

 

[Aladdin]

In the case of that mutation they were talking about how this mutation was seen popping up in variations of the virus that they had found in immunocompromised patients, probably during a lengthy infection, quite possibly when attempts to help the patient included plasma from recovered patients.

So them mentioning it is in connection with the risk of that sort of mutation appearing in such patients, about how such mutations pop up in the first place. And the implications of a strain with such mutations taking hold that can escape peoples immunity more broadly.

Its not being mentioned in the context of some additional implications and risks specific to people with compromised immune systems should they catch a version of the virus that takes off in the wild and carries that particular mutations, if thats why you were asking.

Sorry if this explanation is still a bit wordy. I can try again if necessary, let me know.

Yes thank you...that's clearer.. in some way.

 

[elbows]

This weeks update to the numbers. I havent looked for any details about the latest entry on the list, VUI-21MAY-01 of the AV.1 lineage.

 

[elbows]

Yes thank you...that's clearer.. in some way.

It does take me a few goes before I can whittle my waffle down to the basics.

A simpler attempt would be: its about where this mutations came from/was first spotted, rather than what implications it has for immunocompromised patients in particular if a wild strain with that mutation is widespread.

 

[2hats]

AV.1 (VUI-21MAY-01) is technically B.1.1.482.1 (ie B.1.1.482 parent lineage). May be associated with B.1.1.28 (parent lineage of P.1). Mainly seen in South Yorkshire (but also E Midlands, NW and SE in very small numbers) plus France. Significant numbers of mutations (~23) in the ORF and spike:

ORF1a	NSP1	D75G
ORF1a	NSP2	G339S, A411V
ORF1a	NSP3	H342Y, P822L, K927I, N1587S
ORF1a	NSP4	A446V
ORF1a	NSP6	△106-108
ORF1b	NSP12	P323L, S434A
ORF1b	NSP13	T481M
ORF1b	NSP14	A119V
S	Spike	D80G, T95I, G142D, △144, N439K, E484K, D614G, P681H, I1130V, D1139H
M	Membrane	A63T, H125Y
N	Nucleocapsid	I157V, R203K,G204R,

Some of the mutations may reduce effectivity of monoclonal antibodies, improve ACE2 affinity and improve transmission.

Detailed analysis here.

 

[Supine]

AV.1 (VUI-21MAY-01) is technically B.1.1.482.1 (ie B.1.1.482 parent lineage). May be associated with B.1.1.28 (parent lineage of P.1). Mainly seen in South Yorkshire (but also E Midlands, NW and SE in very small numbers) plus France. Significant numbers of mutations (~23) in the ORF and spike:

ORF1a	NSP1	D75G
ORF1a	NSP2	G339S, A411V
ORF1a	NSP3	H342Y, P822L, K927I, N1587S
ORF1a	NSP4	A446V
ORF1a	NSP6	△106-108
ORF1b	NSP12	P323L, S434A
ORF1b	NSP13	T481M
ORF1b	NSP14	A119V
S	Spike	D80G, T95I, G142D, △144, N439K, E484K, D614G, P681H, I1130V, D1139H
M	Membrane	A63T, H125Y
N	Nucleocapsid	I157V, R203K,G204R,

Some of the mutations may reduce effectivity of monoclonal antibodies, improve ACE2 affinity and improve transmission.

Detailed analysis here.

Just turned up to post this. Yorkshire’s turn.

 

[Miss-Shelf]

@InfectionDave

Dr Andrew Lee, reader in global public health at the University of Sheffield, tweeted today: “Emergence of a new #covid variant #B11482 in South Yorkshire reported by team from @sheffielduni & Sheffield Teaching Hospitals. Great work @Thushan_deSilva @cariadmevans @InfectionDave & others."

This is a great time to be a [whoever has a professional interest in looking for virus variants and such like ]

 

[Supine]

 

[elbows]

AV.1 (VUI-21MAY-01) is technically B.1.1.482.1 (ie B.1.1.482 parent lineage). May be associated with B.1.1.28 (parent lineage of P.1). Mainly seen in South Yorkshire (but also E Midlands, NW and SE in very small numbers) plus France. Significant numbers of mutations (~23) in the ORF and spike:

ORF1a	NSP1	D75G
ORF1a	NSP2	G339S, A411V
ORF1a	NSP3	H342Y, P822L, K927I, N1587S
ORF1a	NSP4	A446V
ORF1a	NSP6	△106-108
ORF1b	NSP12	P323L, S434A
ORF1b	NSP13	T481M
ORF1b	NSP14	A119V
S	Spike	D80G, T95I, G142D, △144, N439K, E484K, D614G, P681H, I1130V, D1139H
M	Membrane	A63T, H125Y
N	Nucleocapsid	I157V, R203K,G204R,

Some of the mutations may reduce effectivity of monoclonal antibodies, improve ACE2 affinity and improve transmission.

Detailed analysis here.

Does the "May be associated with B.1.1.28" bit which is detailed in the paper imply recombination? I see the B.1.1.28 samples that shared most of the mutations and actually had location data were from Coventry.

 

[2hats]

Not sure - probably not enough of it around to be highly likely (cf recombination events seen in B.1.1.7). Besides, I think if it were (clearly identified/agreed to be) recombinant then it should have been XB.1 as per pango rules? Can't see any B.1.1.28 in GISAID clearly indicating origin from/near Coventry?

 

[elbows]

Can't see any B.1.1.28 in GISAID clearly indicating origin from/near Coventry?

I havent looked on GISAID, I just took note of this bit from the analysis you linked to:

Importantly, three recent B.1.1.28 samples (QEUH-148F257, QEUH-14C1E55, QEUH-144D7A1) appear to form an intermediate cluster between the South Yorkshire samples and the sample from France suggesting that this could be a common ancestor of the two clusters.

And then I looked up QEUH-148F257 etc on the list of samples they say they used here 6 and two of them say Coventry region.

 

[elbows]

This weeks variant figures. Big increase in B.1.617.2, approx doubling of AV.1, another new variant added (C.36.3), and one removed due to possible extinction. (Information pertaining to VUI-21MAR-01, B1.324.1 with E484K has been removed as this variant has been reclassified as provisionally extinct.)

Variants: distribution of case data, 27 May 2021

www.gov.uk

 

[2hats]

C.36.3 has the L452R point mutation in common with 'US' variants B.1.526.1, B.1.429, B.1.427 ('NY', 'CA', 'CA') as well as B.1.617.x. It also has the 69-70 deletion so should show up on the TaqPath with the S gene dropout.

There is (what could classified as being) a new variant (sublineage) of B.1.617.2 just drifting across the radar (not yet uniquely named - see page 37, table 11 of PHE VOC Technical Briefing 13 ). It features a spike RBD point mutation of concern (K417N) in common with P.1 and B.1.351 (both of which have a greater degree of immune escape than most other variants). Probably a travel introduction (has been seen in several countries) that has already established elsewhere with less sequencing surveillance.

Separately there might be a hint in the NHS T&T data that B.1.617.2 takes longer for symptoms to appear (page 28, figure 6 of PHE VOC Technical Briefing 13), and the window of transmission could be on the longer side (cf B.1.1.7), both giving it some advantage.

 

[2hats]

A study of the performance of monoclonal antibodies (mAbs), convalescent sera and vaccine mediated sera with respect to B.1.617.2 from Institute Pasteur.

• B.1.617.2 was resistant to neutralisation by some mAbs (notably including Bamlanivimab) which were impaired in binding to the B.1.617.2 Spike.
• Sera from convalescent patients collected up to 12 months post infection and from BNT162b2 vaccine recipients (both doses) were 3 to 6 fold less potent against B.1.617.2, relative to the B.1.1.7 variant and earlier (D614G) types.
• Sera from individuals having received one dose of AZD1222 barely inhibited B.1.617.2 (note: second doses of AZD1222 had not yet been administered in France at the time of publication).

Here below, neutralisation against given variants for (a) convalescents, (c) vaccinees, and then (b), (d) classification of proportions of persons in each cohort considered capable of neutralising the variant types in question (blue) and 'failed to neutralise' (grey).


DOI: 10.1101/2021.05.26.445838.

Note - also a not insignificant drop in neutralisation against B.1.351 for BNT162b2 vaccinees by 4 months which might suggest the need for a multivalent formulation to improve coverage.

 

[2hats]

I dont suppose you've seen any simple estimates of what range the 'natural, unimpeded R' of the India strain might be? Or for that matter what sort of range that would have been for the Kent variant?

Just noticed that Kucharski estimates baseline R for B.1.1.7 at around 4-5. On which basis B.1.617.2 could easily be above 5, maybe even 6-point-something.

 

[elbows]

Just noticed that Kucharski estimates baseline R for B.1.1.7 at around 4-5. On which basis B.1.617.2 could easily be above 5, maybe even 6-point-something.

Thanks very much. Numbers that high or potentially even higher did enter my imagination which is why I asked. Wasnt sure if I'd gotten carried away with how high those numbers could be, and part of my brain still recalls how things were framed around such numbers early in the pandemic. So hearing about latest variants in those terms helps me update my sense of how much pandemic weight we need vaccines and ongoing behavioural changes to carry.

 

[2hats]

A new study from Imperial which suggests that the P681R point mutation, on the D614G backbone, improves the efficiency of the S1/S2 furin cleavage site, likely a mechanism for enhancing transmissibility and pathogenicity, in B.1.617.2 (and associated sub-lineages). The P681H of B.1.1.7 likely contributes to the increased transmissibility of that variant (over earlier types but to a lesser degree than for B.1.617.x).
DOI: 10.1101/2021.05.28.446163.

 

[2hats]

Thanks very much. Numbers that high or potentially even higher did enter my imagination which is why I asked. Wasnt sure if I'd gotten carried away with how high those numbers could be, and part of my brain still recalls how things were framed around such numbers early in the pandemic. So hearing about latest variants in those terms helps me update my sense of how much pandemic weight we need vaccines and ongoing behavioural changes to carry.

Just to underline, an epidemiologist writes:

 

[2hats]

There is (what could classified as being) a new variant (sublineage) of B.1.617.2 just drifting across the radar (not yet uniquely named - see page 37, table 11 of PHE VOC Technical Briefing 13 ). It features a spike RBD point mutation of concern (K417N) in common with P.1 and B.1.351 (both of which have a greater degree of immune escape than most other variants). Probably a travel introduction (has been seen in several countries) that has already established elsewhere with less sequencing surveillance.

This is a variant that looks like it might have originated out of Nepal/India - has unfortunately been described as the 'Nepal' variant in some quarters. Though there is next to no sequencing surveillance in Nepal, it was picked up in Japan amongst a number of travellers from there. So far 90 cases worldwide also detected in Portugal, Poland, Japan, India, UK, Swittzerland, US and Canada.

Separately there might be a more agressive sub-lineage of B.1.617.2 emerging, which features G215C in the nucleoprotein and what might prove to be some functional changes in the ORF.

 

[elbows]

A new study in the Lancet: "Neutralising antibody activity against SARS-CoV-2 VOCs B.1.617.2 and B.1.351 by BNT162b2 vaccination"

Neutralising antibody activity against SARS-CoV-2 VOCs B.1.617.2 and B.1.351 by BNT162b2 vaccination

The SARS-CoV-2 B.1.617.2 Variant of Concern (VOC), first detected in India, is now dominant in the UK, having rapidly1 displaced the B.1.1.7 strain2 that emerged in the UK with the second COVID-19 wave in late 2020. The efficacy of currently licensed COVID-19 vaccines against B.1.617.2 is...

www.thelancet.com

Two doses of BNT162b2 elicited ELISA-detected anti-Wild-type spike antibodies in all participants, and NAb activity against all strains, including the three VOCs tested, in all except six (3%) and nine (5%) of 159 participants who lacked NAb activity against B.1.617.2 and B.1.351, respectively (appendix p 2). NAbTs of sera correlated well between Wild-type and variants (appendix p 2; RS>0·82, p<2 × 10−16), as well as between VOCs (B.1.617.2 vs B.1.351: RS=0·85, p<2 × 10−16). However, NAbTs were 5·8-fold reduced against B.1.617.2 relative to Wild-type (95% CI 5·0–6·9), significantly more reduced than against B.1.1.7 (2·6-fold vs Wild-type, 95% CI 2·2–3·1), and on a similar order to the reduction observed against B.1.351 (4·9-fold vs Wild-type, 95% CI 4·2–5·7).

Notably, across all variants, increased age significantly correlated with reduced NAbT (appendix p 2; −0·33<RS<–0·27; 2·2 × 10−5<p<5·6 × 10−4), whereas no correlation was observed for sex or body-mass index (appendix p 4). NAbTs reduced over time after administration of the second dose of BNT162b2: participants (n=14) who attended an additional study visit 8–16 weeks after their second BNT162b2 dose showed significantly reduced NAbTs against all variants (appendix p 2; 0·0002<p<0·0134). While the final NAbTs against Wild-type, D614G, and B.1.1.7 remained within the quantitative range of our assay (IC50>40), two participants' NAbTs against VOCs B.1.617.2 and B.1.351 dropped below 40 on their later study visit about 3 months after their second BNT162b2 dose.

We found that neutralisation of VOCs was markedly different after only one dose of BNT162b2 (appendix p 2): although 177 (95%) of 186 participants tested positive for anti-spike antibodies by ELISA and mounted a detectable NAb response against Wild-type (median IC50=68 [IQR 42–140]) and D614G (median IC50=71 [IQR 46–111]), median NAbTs against all VOCs were below the quantitative limit of detection. Stratification of NAbTs into three groups (IC50 low [<40], medium [40–256], high [>256]) and assessment of the significance of the shift in their distribution relative to Wild-type by ordered logistical regression was more informative (appendix p 2). Whereas only 39 (21%) of 186 samples had low NAbTs against Wild-type, this proportion rose to 50% against B.1.1.7 (p=1·7 × 10−6) and further to 75% against B.1.351 (p<3 × 10−16) and 68% against B.1.617.2 (p<5 × 10−16). Notably, the downwards shift in titres was also significant when compared to B.1.1.7 for B.1.351 (p=3·7 × 10−4) and B.1.617.2 (p=1·2 × 10−5), confirming reduced NAb activity against B.1.617.2 relative to the present B.1.1.7 strain after one vaccine dose. Notably, participants with low NAbTs tend to be older than those who produced medium or high responses (appendix p 2), and logistical regression analysis suggests age is a significant factor in reduced NAbTs, independent of strain in our samples (appendix p 7; p=0.006), following a single dose of BNT162b2.

 

[2hats]

Up to 5% failure to generate any significant immune response to full vaccination is expected (note cohort relatively young, median age 43, and healthy, average BMI <25).

Seperately, it looks like the N:G215C flavoured B.1.617.2 might be the one currently flourishing in the UK.

 

[2hats]

There is (what could classified as being) a new variant (sublineage) of B.1.617.2 just drifting across the radar (not yet uniquely named - see page 37, table 11 of PHE VOC Technical Briefing 13 ). It features a spike RBD point mutation of concern (K417N) in common with P.1 and B.1.351 (both of which have a greater degree of immune escape than most other variants). Probably a travel introduction (has been seen in several countries) that has already established elsewhere with less sequencing surveillance.

B.1.617.2 with K417N (in spike) now named AY.1 (alias of B.1.617.2.1).

 

[elbows]

B.1.617.2 with K417N (in spike) now named AY.1 (alias of B.1.617.2.1).

 

[elbows]

I've stopped sticking the full chart of variant UK number updates in this thread given the dominance of Delta makes it somewhat pointless at the moment, eg:

COVID-19 variants: genomically confirmed case numbers

Genomically confirmed case numbers for SARS-CoV-2 variants of concern and variants under investigation.

www.gov.uk

 

[elbows]

Just noticed that Kucharski estimates baseline R for B.1.1.7 at around 4-5. On which basis B.1.617.2 could easily be above 5, maybe even 6-point-something.

This new BBC article mentions a possible range of between 5 and 8, which comes via disease modellers at Imperial.

Covid: Is there a limit to how much worse variants can get?

The coronavirus has changed and changed again, getting more transmissible each time.

www.bbc.co.uk

 

[elbows]

By the way 2hats, I am curious about their approach to ongoing surge testing in certain locations, given that the Delta variant now dominates more broadly.

Eg Leek, Staffordshire announced recently: Surge testing to be deployed in Staffordshire

I suppose I am curious whether they would use this stuff and just describe it as testing for Delta variant, if they are actually concerned, for example, by cases of AY.1 in the area?

 

[2hats]

No idea. No recent AY.1 sequences posted this month in the UK (39 so far, the last being on 28 May; last one globally was in the US on 01 June).

 

[elbows]

Cheers. Its not something I consider especially likely at the moment, it was just something that briefly sprang to mind that I thought I better keep in mind for the future. And there are other reasons why they'll still want to do surge testing in areas with particularly large outbreaks linked to Delta. So I wont be turning these thoughts into a wacky theory or try to make bad guesses.

 

[elbows]

A new study from Imperial which suggests that the P681R point mutation, on the D614G backbone, improves the efficiency of the S1/S2 furin cleavage site, likely a mechanism for enhancing transmissibility and pathogenicity, in B.1.617.2 (and associated sub-lineages). The P681H of B.1.1.7 likely contributes to the increased transmissibility of that variant (over earlier types but to a lesser degree than for B.1.617.x).
DOI: 10.1101/2021.05.28.446163.

Heres another one:

During the current SARS-CoV-2 pandemic, a variety of mutations have been accumulated in the viral genome, and at least five variants of concerns (VOCs) have been considered as the hazardous SARS-CoV-2 variants to the human society. The newly emerging VOC, the B.1.617.2 lineage (delta variant), closely associates with a huge COVID-19 surge in India in Spring 2021. However, its virological property remains unclear. Here, we show that the B.1.617 variants are highly fusogenic and form prominent syncytia. Bioinformatic analyses reveal that the P681R mutation in the spike protein is highly conserved in this lineage. Although the P681R mutation decreases viral infectivity, this mutation confers the neutralizing antibody resistance. Notably, we demonstrate that the P681R mutation facilitates the furin-mediated spike cleavage and enhances and accelerates cell-cell fusion. Our data suggest that the P681R mutation is a hallmark characterizing the virological phenotype of this newest VOC, which may associate with viral pathogenicity.

SARS-CoV-2 spike P681R mutation enhances and accelerates viral fusion

bioRxiv - the preprint server for biology, operated by Cold Spring Harbor Laboratory, a research and educational institution

www.biorxiv.org