XBB.2.3.3 Sublineage w/new S2' FCS—S:N450D, S:K478R, S:P812R, S:V1264L + 4x ORF1ab (6 countries, 48 seq, Jan 21)

[ryhisner]

Description

Sub-lineage of: XBB.2.3.3
Earliest sequence: 2023-7-30, Netherlands, Noord-Brabant — EPI_ISL_18098305
Most recent sequence: 2023-8-13, Netherlands, Noord-Holland — EPI_ISL_18115963
Countries circulating: Netherlands (2)
Number of Sequences: 2
GISAID AA Query: Spike_P812R, Spike_P521S
GISAID Nucleotide Query: G3620A, A6326G
CovSpectrum Query: Nextcladepangolineage:XBB.2.3.3* & S:P812R
Substitutions on top of XBB.2.3.3:
Spike: N450D, K478R, P812R, V1264L
ORF1a: T224I, G1119S, T2021A
ORF1b: G977C
Nucleotide: C936T, G3620A, A6326G, A13021G, C15540T, G16396T, A17622G, A22910G, A22995G, T23830C, C23997G, G25352C, C26936T

USHER Tree
https://nextstrain.org/fetch/raw.githubusercontent.com/ryhisner/jsons2/main/XBB.2.3.3_N450D_K478R_P812R_V1264L.json?c=gt-S_812&gmax=25384&gmin=21563&label=id:node_4102599

Evidence
XBB.2.3* lineages has curiously been much slower than XBB.1*+S:S486P lineages to pick up advantageous spike mutations, particularly S:F456L (in 0.69% of XBB.2.3* in the past 3 months compared to 18.7% of XBB.1*+S:F486P) and L455F-F456L (1067 sequences of XBB.1*+S:F486P w/Flip compared to zero XBB.2.3*). S:N450D has been extremely rare in both, however, appearing in just 51 sequences in the past three months.

But the most interesting aspect of this 2-sequence (so far) saltation branch of XBB.2.3.3 is the presence of S:P812R, which @thomaspeacock informed us creates a new furin-cleavage site (FCS) at the S2' location. See his explanation at Pango Github issue #1627 here: https://github.com/cov-lineages/pango-designation/issues/1627 .

This lineage also has S:K478R, which has proven to confer a growth advantage in XBB lineages, and S:V1264L, which has proven to be an advantageous mutation in the past, and which has a solid fitness advantage according to the Bloom Lab amino-acid fitness calculator.

Genomes

Genomes

EPI_ISL_18098305, EPI_ISL_18115963, EPI_ISL_18130456, EPI_ISL_18136960, EPI_ISL_18136963, EPI_ISL_18286700, EPI_ISL_18299958, EPI_ISL_18331374, EPI_ISL_18392989, EPI_ISL_18393096, EPI_ISL_18393098, EPI_ISL_18398856, EPI_ISL_18398858, EPI_ISL_18403515, EPI_ISL_18403933, EPI_ISL_18419955, EPI_ISL_18421656, EPI_ISL_18441622, EPI_ISL_18444758, EPI_ISL_18444761-18444762, EPI_ISL_18444840, EPI_ISL_18446173, EPI_ISL_18467510-18467513, EPI_ISL_18467516-18467517, EPI_ISL_18467525, EPI_ISL_18467588, EPI_ISL_18471202, EPI_ISL_18520168, EPI_ISL_18535805, EPI_ISL_18536101, EPI_ISL_18584927, EPI_ISL_18584952, EPI_ISL_18640365, EPI_ISL_18674275, EPI_ISL_18674905, EPI_ISL_18674917, EPI_ISL_18694629, EPI_ISL_18701935, EPI_ISL_18712638, EPI_ISL_18754699, EPI_ISL_18754879, EPI_ISL_18763381,

[FedeGueli]

@ryhisner consider that there is also GJ.1.2.1 (same XBB.2.3.3 family) that has as defining mutation S:N450D and further acquired S:T478R so leaving out the S2 interesting mutations , this notably converges toward its "sibling"

[oobb45729]

Maybe it can be explained by my conjecture about that losing ORF8 trades innate immune evasion capability for infectiousness.
cov-lineages/pango-designation#1451

Could it mean that mutations like ORF8:G8* or C27889T work better when the spike is highly antibody-evasive that it can tolerate the ORF8 loss? Maybe this is the reason why ORF8:G8* is doing well on XBB. Could it also mean that if the spike is no longer so antibody-evasive, the ORF8 loss becomes detrimental to the virus? Could this be the reason that the vaccines did a much better job limiting the spread of Alpha (with ORF8:Q27*) than Delta?

BA.5 also faded quite fast when the spike is no longer so antibody-evasive. Maybe for lineages without a full ORF8, they need antibody-evasive mutations more to keep up, but XBB.2.3 has a full ORF8, so it doesn't need S:F456L that much?

[ryhisner]

This one tripled from two to six sequences in the past two days.

[FedeGueli]

weirdly the AA query (6) gives one more seq than the nuc query (5) G3620A, A6326G , anyway it seems doubling fast.

[JosetteSchoenma]

Yes @FedeGueli The sixth one misses G3620A and has an N at A6326G. They all have A17622G, if you would like to add it, but query Spike_P812R, Spike_P521S does the job.
Thanks, @ryhisner. The majority of recent Dutch XBB.2.3 have S:478R, from several different sublineages.
EPI_ISL_18137115
EPI_ISL_18136963
EPI_ISL_18136960
EPI_ISL_18130456
EPI_ISL_18115963
EPI_ISL_18098305
New tree, including those EPI_ISL numbers and the dates.

[FedeGueli]

Yes def the Combo 478-521 works well (also on XBB.1.16 backbone) , likely if XBB.2.3 would have got it before it could be in a leading position now.

[FedeGueli]

Thx @JosetteSchoenma

[FedeGueli]

it unbelievably seems slow. or this new fcs thing makes the virus super mild or slow it toward lower fitness !

[JosetteSchoenma]

Reasonably big upload today from the Netherlands. No new ones.
But still expecting an upload from Noord-Holland.

[FedeGueli]

Closing this for now @ryhisner ping me if something changes!

[ryhisner]

Probably still a dead lineage, but two showed up in Scotland today with collection dates of Sept 25-26, and there are three more on the Usher tree with October collection dates that haven't been uploaded to GISAID yet. EPI_ISL_18393096, EPI_ISL_18393098

[JosetteSchoenma]

And apparently there was a Dutch one in between, so 12 in total now then.

[FedeGueli]

Reopened

[FedeGueli]

Although it is not super fast it has been sequenced in multile countries recently now 15 seqs

[ryhisner]

Credit to @JosetteSchoenma for spotting a recent surge in this one, which is now >32 sequences. (There are at least some on the Usher tree but not on GISAID, but the fat that many of the samples occur on the Usher tree three separate times makes it hard to count them.) The most recent sequences have mostly been from Scotland, with one from Belgium and a coupe from the Netherlands. One also showed up on the West Coast of the USA in the state of Washington.

[FedeGueli]

+1 Anhui

[FedeGueli]

One only sample in November closing it

[FedeGueli]

38 now last 2 from Slovakia

[FedeGueli]

44 sequences and after only two sequences in november showed up in 4 samples in December mostly from Netherlands. Reopening for a whilel

[FedeGueli]

New tree:

2023-12-25

cc @ryhisner one curious thing here is that the brach that survived and it is circulatingin NDL and Uk is defined by two silent mutations in the RBD:
T22925C > S:L455L
A23092T > S:V510V

What this could mean?

[FedeGueli]

48. now. most of the recent samples in the branch with silent spike substitutions: T22925C

[FedeGueli]

Please propose on the main repo!