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Bloom Lab Profile picture
@jbloom_lab
Sep 28 • 5 tweets • 2 min read Twitter logo Read on Twitter
There have been many experimental papers on BA.2.86 over last month. This one by David Ho's group is one of most comprehensive:

I'm going to quickly summarize key points for people having hard time keeping up w all the recent BA.2.86 papers.biorxiv.org/content/10.110…
1⃣ Serum neutralization of BA.2.86 roughly comparable to XBB.1.5, & comparable or slightly better than newer XBB variants like EG.5.1

Similar results (within few-fold) reported by other groups too, eg @yunlong_cao @BenjMurrell @BarouchLab @sigallab @ShanLuLiu1 @SystemsVirology
2⃣ But BA.2.86 escapes somewhat different antibodies than XBB variants: BA.2.86 has more escape from SD1 & RBD class 2/3 Abs, but less escape from RBD class 1/4 Abs

So maybe BA.2.86 & XBB have slightly different immunological "niches"

Also see:
3⃣ BA.2.86 actually has better ACE2 affinity than BA.2 and XBB.1.5. Possibly this could impact transmissibility, and certainly it could impact tolerance for future antibody escape mutations.

This result has also been reported by @yunlong_cao:
4⃣ David Ho's paper speculates BA.2.86 may have more up (exposed) RBD based on RBD class 1/4 antibody neutralization & higher ACE2 affinity.

Note @yunlong_cao has speculated opposite based on cryo-EM ().

An interesting question for further investigation!

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More from @jbloom_lab

Bloom Lab Profile picture
Aug 30
Here are data from new XBB.1.5 spike deep mutational scanning by @bdadonaite in our group

Go to see how mutations affect:

1⃣ Neutralization by human XBB breakthrough sera

2⃣ Spike-mediated pseudovirus entry in 293T-ACE2 cells

3⃣ Spike affinity for ACE2dms-vep.github.io/SARS-CoV-2_XBB…
It will be a few weeks before we finish & post pre-print for study, but we wanted to share data now for those interested in interpreting current SARS2 evolution.

Measurements were made using lentiviral deep mutational scanning () with XBB.1.5 spike.sciencedirect.com/science/articl…
Experiments map sites in XBB spike where mutations escape neutralization by sera of humans w recent XBB infection

(Antibody response depends on exposure history, so escape may differ for other exposures not studied here)

Greatest escape is at sites 473, 357, 455/456, 420 Image
Read 10 tweets
Bloom Lab Profile picture
Aug 16
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)
Full analysis of the mutations is in these slides:

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)slides.com/jbloom/new_2nd…
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. Image
Read 12 tweets
Bloom Lab Profile picture
Aug 3
In new study, we develop rigorous method to jointly analyze deep mutational scanning of different protein homologs or conditions

We use it to identify mutations w effects on spike-mediated viral entry that differ by >1,000-fold among #SARSCoV2 strains.

biorxiv.org/content/10.110…
As background, common question in evolution is if some mutations have different effects in different homologs or conditions

Eg, our lab has measured how most mutations to Delta, BA.1 & BA.2 spike affect viral entry. Which mutations have different effects in these viral variants?
If deep mutational scanning experiments were perfect, we’d just compare the measured effects of each mutation in the different spikes to see if they were non-identical.

But in practice, experiments have noise: so how do we tell true biological differences from noise?
Read 12 tweets
Bloom Lab Profile picture
Jul 27
This paper from Linfa Wang’s group to which @tylernstarr & I contributed illustrates interesting points about

1⃣ Importance of imprinting for antibody specificity to SARS-like CoV

2⃣ How it may be easier to broadly neutralize animal sarbecoviruses than human #SARSCoV2 variants
Briefly, the study (which was led by Wan Ni Chia @CheeWahTan2 @LokShee @linfa_wang), isolated antibodies from person who had been infected by SARS-CoV-1 in ~2003, then received Pfizer SARS-CoV-2 vaccine in 2021.
So unlike most people in the world, whose first immunological exposure to a SARS-related CoV was to an early SARS-CoV-2 strain via either infection or vaccination in 2020 or 2021, this person’s immune system had been “imprinted” by SARS-CoV-1 prior to their COVID vaccine.
Read 15 tweets
Bloom Lab Profile picture
Jul 6
A few brief thoughts on antigenic impact of F456L mutation that is becoming more common in #SARSCoV2 XBB strains.

@yunlong_cao et al *already* measured impact of this mutation on human serum antibody neutralization in their recent preprint, and it causes ~1.5-fold titer drop.
Specifically, see Extended Data Fig 6 of

Spike of XBB.1.5.10 is XBB.1.5 + F456L, so compare those strains to see effect of F456L.

Across three cohorts, F456L causes titer drops of:

207 -> 148 (1.4-fold)

251 -> 178 (1.4-fold)

562 -> 379 (1.5-fold) biorxiv.org/content/10.110…
Image
So F456L causes measurable titer drop in serum antibody neutralization

That said, 1.5-fold decrease is modest effect

Greater escape in XBB will require multiple mutations. Candidate mutations are shown below based on deep mutational scanning:
Read 4 tweets
Bloom Lab Profile picture
Jun 5
I wanted to post notes on potentially beneficial non-spike mutations in #SARSCoV2 variants XBB.1.16 & XBB.1.9.1, two of fastest growing variants.

These are from estimates of effects of mutations to all SARS-CoV-2 proteins from @richardneher & myself
Both XBB.1.16 & XBB.1.9.1 have I5T mutation in ORF9b innate-immune antagonist accessory protein. XBB.1.16 also has N55S in this protein.

According to our estimates (jbloomlab.github.io/SARS2-mut-fitn…), I5T in ORF9b is beneficial while N55S is roughly neutral Image
XBB.1.9.1 has the T35I mutation in nsp9 (equivalent to T4175I in ORF1a).

According to our estimates (jbloomlab.github.io/SARS2-mut-fitn…), T35I in nsp9 is beneficial. Image
Read 6 tweets

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