Bloom Lab

I wanted to summarize what is known about the new XBB.1.5 variant of SARS-CoV-2, which is starting to generate a lot of interest.

(There are no new scientific results in this thread, it simply aggregates previously reported results for those not following topic closely.)

Jan 2, 2023 at 8:03pmWeb
Show threadBloom LabJan 2, 2023

Reason people are discussing XBB.1.5 is because it's so transmissible. Below are estimates of current Rt (measure of transmissibility) of different variants in US from @trvrb's group.

XBB.1.5 is more transmissible than other variants like BQ.1.1 that until recently dominated in US.

Show threadBloom LabJan 2, 2023

High transmissibility means XBB.1.5 is becoming responsible for larger fraction of COVID-19 cases.

This continues a pattern of strain replacement we've seen over last few years of SARS-CoV-2 evolution (see below).

Eg, there will always be new variants spreading, and right now it's XBB.1.5.

Show threadBloom LabJan 2, 2023

Whether increase in relative fraction of cases due to XBB.1.5 will also lead to surge in absolute cases is still not certain.

But sometimes new variants drive increase in total cases, and in general human coronaviruses (and other respiratory viruses) surge in winter.

Show threadBloom LabJan 2, 2023

A scientifically interesting aspect of XBB.1.5 is we pretty much understand what mutation made it so transmissible, the mechanism by which the mutation acts, and why it took so long for the mutation to emerge.

XBB.1.5 is a descendant of XBB.1, which descends from XBB, which evolved through recombination between two descendants of the earlier Omicron BA.2 variant.

Show threadBloom LabJan 2, 2023

The parental XBB and XBB.1 variants were already notable because they were fairly transmissible and had lots of antibody escape, as shown by @yunlong_cao et al & others (https://www.nature.com/articles/s41586-022-05644-7).

However, XBB and XBB.1 were not as transmissible as XBB.1.5.

Imprinted SARS-CoV-2 humoral immunity induces convergent Omicron RBD evolution - Nature

Convergent mutations in hotspots of the SARS-CoV-2 Omicron receptor-binding domain can cause immune evasion and maintain sufficient ACE2-binding capability.

Nature
Show threadBloom LabJan 2, 2023

One of the sites that is mutated in the parental XBB/XBB.1 variants is 486 in the RBD.

486 has been a major site of antibody escape going back to the earliest variants (see image below from our antibody-escape calculator https://jbloomlab.github.io/SARS2_RBD_Ab_escape_maps/escape-calc/).

Show threadBloom LabJan 2, 2023

But while some antibody escape sites such as 484 were fixing mutations in major variants by late 2020, it took longer for major variants to emerge w mutations at site 486: eg, BA.4/5 w F486V in spring 2022, & then XBB w F486S later in 2022.

It’s easy to understand why it took longer for variants to emerge at site 486: mutations at 486 reduce ACE2 affinity, so benefit they provide in antibody escape comes at cost to receptor binding.

See our deep mutational scanning: https://www.science.org/doi/10.1126/science.abo7896

Show threadBloom LabJan 2, 2023

So variants like XBB/XBB.1 fixed mutation (F486S) that was beneficial for antibody escape but detrimental to ACE2 affinity. In other words, they made an evolutionary tradeoff.

But as Ryan Hisner noticed months ago, our deep mutational scanning shows one mutation at site 486 is not so bad for ACE2 affinity, especially in background of BA.2, F486P: https://twitter.com/LongDesertTrain/status/1556473662253015040

Ryan Hisner on Twitter

“So of the 19 possible amino acid mutations at F486, P is #1 for ACE2 binding (well ahead of all others), #5 for RBD expression (very close to the top and #1 among all six observed F486 mutations), and appears to be #2 for evading antibodies. 13/16”

Twitter
Show threadBloom LabJan 2, 2023

Catch is that F486P requires *two* nucleotide mutations to the same codon, which is rare event even for RNA virus like SARS-CoV-2: https://twitter.com/LongDesertTrain/status/1556473625456377863

That's why it took so long for variants to start fixing F486P.

Ryan Hisner on Twitter

“One reason this mutation is so surprising is that it requires a 2-nucleotide change. Each amino acid is encoded by three nucleotides, & the vast majority of mutations (>99.99% I’d guess) involve just one nucleotide change. Two-nuc mutations are exceedingly rare. 2/16”

Twitter
Show threadBloom LabJan 2, 2023

The difference between XBB.1.5 and its immediate parent XBB.1 is that it has traded the more costly F486S mutation for F486P. Therefore, XBB.1.5 isn’t expected to have more antibody escape than XBB.1 (which already had mutated F486), but it should have greater ACE2 affinity.

And as @yunlong_cao nicely describes, this is exactly what is directly measured: https://twitter.com/yunlong_cao/status/1607915567696203776

Yunlong Richard Cao on Twitter

“The superior growth advantage of XBB.1.5 has been well-documented by many colleagues @JPWeiland @LongDesertTrain @EricTopol. Here I'll add some experimental data: 1) XBB.1.5 is equally immune evasive as XBB.1, but 2) XBB.1.5 has a much higher hACE2 binding affinity. 1/”

Twitter
Show threadBloom LabJan 2, 2023
So it’s greater ACE2 affinity (and perhaps RBD stability) that is giving XBB.1.5 its boost in transmissibility.
Show threadSkylar HopkinsJan 2, 2023
@jbloom_lab this is a very cool plot! Did you pull the data to make it? I don't see a way to change the timeline to start back in 2020 on the web app.
Show threaddr 🛠️🛰️📡🎧Jan 2, 2023
@jbloom_lab @trvrb Is there a 2D version of this graph that plots Rt vs lethality?
Show threadElizabeth Wrigley-FieldJan 2, 2023
@davidr @jbloom_lab @trvrb Very hard to pin down lethality across variants when population immunity is always shifting so much
Show threaddr 🛠️🛰️📡🎧Jan 2, 2023
@wrigleyfield @jbloom_lab @trvrb Wouldn't that also apply to transmissibility?
Show threadElizabeth Wrigley-FieldJan 2, 2023

@davidr @jbloom_lab @trvrb

Yes, good point. But less so, I would expect, since vaccines (and presumably infection-based immunity too) are less effective in reducing transmission than hospitalization etc

Show threadDrKerryaneJan 2, 2023
@jbloom_lab @trvrb May I use this graph in an Intro Bio course? If so, should I credit your lab? Thank you for this thread - it was very helpful (and interesting!).
Show threadCaptain ObservantJan 2, 2023
@jbloom_lab @trvrb This pandemic is less a linear journey from start to finish, and more like a game of snakes and ladders. We just landed on a long snake named XBB 1.5.