I wanted to provide assessment of spike amino-acid mutations in new highly mutated 2nd generation BA.2 SARS-CoV-2 variant

This is analysis for those (like me) scientifically interested in SARS2 evolution

(Anyone else is completely within reason to ignore this variant right now)

https://twitter.com/LongDesertTrain/status/1690989522035617792

Full analysis of the mutations is in these slides: https://slides.com/jbloom/new_2nd_gen_ba2_variant

Analysis is based mostly on deep mutational scanning experiments

TLDR: lots of antigenic change, and some interesting RBD mutations (addition of N-linked glycan & deletion in receptor-binding motif)

First, to emphasize, only THREE sequences of variant identified so far. There is not currently evidence of wide transmission.

As this thread outlines, people who study SARS2 evolution may want to pay attention to features of this variant. Everyone else can ignore if they wish.

As has been noted already, this variant has lots of amino-acid mutations in spike: 33 relative to its putative ancestor BA.2. It is also very different from XBB.1.5.

This makes it an evolutionary jump comparable in size to that which originally gave rise to Omicron.

Below is list of spike amino-acid mutations relative to BA.2, w my annotations of likely effects based on experimental data from Bernadeta Dadonaite, Tyler Starr, Yunlong Cao, and David Veesler.

One thing that is obvious is that many of these mutations cause antibody escape.

I’m going to call out three mutations that I think are especially interesting.

K356T creates a N-linked glycosylation site (at N354) in the RBD, with the resulting glycan likely to completely mask that antibody epitope.

There is deletion of V483 in RBD’s receptor-binding motif

Unpublished data from Tyler Starr and Bernadeta Dadonaite (linked in slides) indicate delV483 will moderately reduce ACE2 affinity & antibody recognition, but effect will be no bigger than some point mutations we’ve seen.

There is P1143L at beginning of S2 stem helix

In our spike deep mutational scanning (https://cell.com/cell/fulltext/S0092-8674(23)00103-4), we found mutating P1143 improves infection by pseudotypes.

We speculated just cell-culture phenomenon, but here is mutation in virus that transmitted at least a bit.

To assess overall antigenic of mutations, we can use antibody-escape calculator (https://jbloomlab.github.io/SARS2-RBD-escape-calc/) informed by data from @yunlong_cao

New variant has at least as much antigenic change relative to BA.2 as does XBB.1.5.

In fact, antigenic advantage of new variant over XBB is likely larger than indicated above, as many people have recently had XBB-specific antibodies boosted by infection. New variant differs from XBB at many key antigenic sites (see https://slides.com/jbloom/new_2nd_gen_ba2_variant for details)

Of course, to spread widely, antigenic advantage would need to be combined w inherent transmissibility close to best XBB variants

With only three sequences so far, there isn’t currently evidence that is case

But important to monitor if more sequences of new variant appear.

I have slightly updated the slides referenced in this thread (https://slides.com/jbloom/new_2nd_gen_ba2_variant) to include the Michigan sequence recently identified as the fourth representative of the highly mutated BA.2.86 lineage.

https://twitter.com/SolidEvidence/status/1692200994632089809

I have slightly updated slides referenced in this thread again (https://slides.com/jbloom/new_2nd_gen_ba2_variant) to include the England sequence recently identified as the fifth representative of the highly mutation BA.2.86 lineage.

https://twitter.com/firefoxx66/status/1692508066778878118

I have updated my slides to reflect identification of 7th sequence of highly mutated BA.2.86 lineage: https://slides.com/jbloom/new_2nd_gen_ba2_variant

For latest on details of BA.2.86 sequences, see this Nextstrain tree from @corneliusroemer @richardneher: https://twitter.com/CorneliusRoemer/status/1693957492399599765

I have updated my BA.2.86 slides: https://slides.com/jbloom/new_2nd_gen_ba2_variant

Slides are still up-to-date with regards to spike protein mutations.

But enough BA.2.86 sequences have now identified that slides are no longer an effective way to track those.

Instead see this tree: https://nextstrain.org/groups/neherlab/ncov/BA.2.86

Also the results of wastewater sequencing: https://twitter.com/dr_leshan/status/1694368402624893045
https://twitter.com/TanjaStadler_CH/status/1694298380841996613