Sublineage of BA.5.6 with S:R346E (34 seq, 12 countries)

[ryhisner]

Description

Sub-lineage of: BA.5.6
Earliest sequence: 2022-8-25, England — EPI_ISL_14858696
Most recent sequence: 2022-9-28, Denmark — EPI_ISL_15267310
Countries circulating: Austria (9), Denmark (2), USA (2), Czech Republic (1), England, Germany (1), Portugal (1), Switzerland (1)
Number of Sequences: 20 (including nine spike-only sequences from Austria)
GISAID Query: Spike_R346E, NSP16_T140I
CovSpectrum Query: Nextcladepangolineage:BA.5.6* & S:R346E
Substitutions on top of BA.5.6:
Spike: R346E
Nucleotide: T979A, A22598G, G22599A

USHER Tree
https://nextstrain.org/fetch/raw.githubusercontent.com/ryhisner/jsons/main/subtreeAuspice1_genome_553f_bfc60%E2%80%94BA.5.6%2BR346E.json

Evidence
S:346 has proven to be one of the most important RBD sites for immune evasion. As at most RBD sites, many theoretically possible mutations involve such a large reduction in ACE2 binding strength or RBD expression (a proxy for stability) that they are untenable, as can be seen in the Bloom Lab RBD ACE2 Heat Map. https://jbloomlab.github.io/SARS-CoV-2-RBD_DMS_Omicron/RBD-heatmaps/

Using the Bloom Lab RBD Heat Map figures for a BA.2 background, I ranked the ACE2 binding strength and RBD expression scores for each possible R346 mutation, from best to worst. Unsurprisingly, R346T comes in first for both categories. R346K ranks high for both, but as both arginine and lysine have similar properties, including being positively charged, it seems likely that R346K is one of the weakest mutations in terms of antibody evasion. Of the 19 possible AA substitutions at S:R346, R346E ranks 4th-highest for both ACE2 affinity and RBD expression.

Furthermore, since glutamic acid is negatively charged, it seems likely to be one of the best substitutions in terms of immune evasion. Indeed, the recent study by Yunlong Cao and Fanchong Jian ranked R346E as the top mutation in terms of evading neutralizing antibodies in convalescent plasma from BA.1, BA.2, and BA.5 infections.
https://www.biorxiv.org/content/10.1101/2022.09.15.507787v3

R346E is a two-nucleotide mutation, which is the most likely reason we have not seen it in any previous lineage thus far. But as immune evasion becomes increasingly important in exerting selection pressure, such rare, two-nucleotide mutations become less unlikely than before.

Given its international spread and recent rapid emergence, I think this lineage should be followed closely.

Genomes

Genomes

EPI_ISL_14858696, EPI_ISL_14941950, EPI_ISL_15157357, EPI_ISL_15161676, EPI_ISL_15173496, EPI_ISL_15196538, EPI_ISL_15196903, EPI_ISL_15208510, EPI_ISL_15213255, EPI_ISL_15235362, EPI_ISL_15258381, EPI_ISL_15265092, EPI_ISL_15267310, EPI_ISL_15288725, EPI_ISL_15288727, EPI_ISL_15288783, EPI_ISL_15288833, EPI_ISL_15289122, EPI_ISL_15289732, EPI_ISL_15290919

[silcn]

Just to note that while R346E isn't in any designated lineage, it was seen before in the small 2nd gen BA.1.1 cluster mentioned in #588, and I made some similar observations about the basic-to-acidic switch at the time.

[corneliusroemer]

Thanks, while small and only single mutation - this is an issue that may be worth designating due to the interesting mutation.

[ryhisner]

Seven sequences of this were uploaded today, five of them spike-only from Austria. Assuming the Austrian spike-only sequences are all a part of this lineage, as seems all but certain, this is now up to 34 sequences from 12 different countries (Israel, Austria, Czech Republic, Denmark, Germany, Italy, Norway, Portugal, Switzerland, England, USA, Australia).

[InfrPopGen]

Thanks for submitting. We've added lineage BA.5.6.4 with 5 newly designated sequences, and 0 updated designations. Defining mutations A22598G (S:R346E), nt:G22599A.

[icestorm972]

FYI:
In Germany RKI DESH data contains now 20 sequences as of today...

(all the dark pink ones on the left side are classified by nextclade as BA.5.6.4)