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Jan 2, 2023 16 tweets 6 min read Read on X
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.)
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 more transmissible than other variants like BQ.1.1 that until recently dominated in US Image
High transmissibility means XBB.1.5 is becoming responsible for larger fraction of COVID-19 cases.

This continues below pattern of strain replacement we’ve seen over last few years of SARSCoV2 evolution.

Eg, there will always be new variants spreading, & right now it’s XBB.1.5. Image
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 ().
The parental XBB and XBB.1 variants were already notable because they were fairly transmissible & had lot of antibody escape, as shown by @yunlong_cao et al & others (nature.com/articles/s4158…). However, XBB and XBB.1 were not as transmissible as XBB.1.5. Image
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 jbloomlab.github.io/SARS2_RBD_Ab_e…). Image
But while some major antibody escape sites such as 484 were fixing mutations in major variants by late 2020, it took a longer time for major variants to emerge with mutations at site 486: eg, BA.4/5 with F486V in spring 2022, and then XBB with 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 below for our deep mutational scanning data from science.org/doi/10.1126/sc… Image
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 @LongDesertTrain 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
Catch is that F486P requires *two* nucleotide mutations to the same codon, which is rare event even for RNA virus like SARS-CoV-2:

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

So it’s greater ACE2 affinity (and perhaps RBD stability) that is giving XBB.1.5 its boost in transmissibility, and causing it to surge.
By the way, whether increase in fraction of cases due to XBB.1.5 will lead to surge in absolute number of cases is still not certain.

But sometimes new variants drive increase in total cases, & in general human coronaviruses (& other respiratory viruses) surge in winter. Image
Also appending this other thread which tries to contextualize role/importance of ACE2 affinity:

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More from @jbloom_lab

Jan 21
In new study, we find dramatic differences in specificities of serum neutralizing antibodies in infants w single infection by a recent SARS-CoV-2 strain versus adults/children imprinted by an early viral strain.

biorxiv.org/content/10.110…
As background, immune response to a virus is “imprinted” by first exposure, since later exposures to new viral strains often activate pre-existing B-cells.

For SARS-CoV-2, most people globally imprinted by an early viral strain from either vaccination or infection in 2020-2021.
However, small but growing fraction of population has instead been imprinted by more recent viral strain.

Specifically, we compared adults/children imprinted by original vaccine then infected w XBB* strain in 2023 vs infants only infected w XBB* in 2023. Image
Read 9 tweets
Nov 21, 2024
I’ve updated SARSCoV2 antibody-escape calculator w new deep mutational scanning data of @yunlong_cao @jianfcpku

My interpretation: antigenic evolution currently constrained by pleiotropic effects of mutations on RBD-ACE2 affinity, RBD up-down position & antibody neutralization
First, the updated escape calculator is at

As shown below, it is remarkable how much antigenicity of RBD has changed over last 4 yrs. jbloomlab.github.io/SARS2-RBD-esca…Image
Updated data for calculator from this paper by @yunlong_cao’s group (nature.com/articles/s4158…), described in this thread by first author @jianfcpku:
x.com/jianfcpku/stat…

Calculator show how much mutations at each RBD site escape binding by set of neutralizing antibodies
Read 13 tweets
Nov 16, 2024
@Nucleocapsoid @HNimanFC @mrmickme2 @0bFuSc8 @PeacockFlu @CVRHutchinson Good observations. See also this thread posted by @SCOTTeHENSLEY:

I have added a few notes to the bottom of that thread.

To recap here:bsky.app/profile/scotte…
@Nucleocapsoid @HNimanFC @mrmickme2 @0bFuSc8 @PeacockFlu @CVRHutchinson @SCOTTeHENSLEY To add to thread linked above, human British Columbia H5 case has a HA sequence (GISAID EPI_ISL_19548836) that is ambiguous at *both* site Q226 and site E190 (H3 numbering)

Both these sites play an important role in sialic acid binding specificity
@Nucleocapsoid @HNimanFC @mrmickme2 @0bFuSc8 @PeacockFlu @CVRHutchinson @SCOTTeHENSLEY If you are searching literature, these sites are E190 and Q226 in H3 numbering, E186 and Q222 in mature H5 numbering, and E202 and Q238 in sequential H5 numbering (see: )dms-vep.org/Flu_H5_America…
Read 6 tweets
Oct 8, 2024
Below is brief analysis of HA mutations in two recent cases of H5N1 influenza in humans w contact w dairy cattle in California.

Summary is that while virus continues to evolve, nothing about HA mutations in these human cases is obviously alarming. Image
As background, CDC reported several recent cases of H5 influenza in California.

CDC and California DOH recently shared sequences of two of these cases via GISAID.
cdc.gov/media/releases…
California human cases share two HA mutations relative to "consensus" dairy cattle virus HA:

D95G & S336N in H3 numbering (D88G & S320N in H5 numbering; D014G & S336N in sequential numbering).

Both these mutations also in some dairy cattle HAs, so not unique to human cases. Image
Read 10 tweets
Sep 15, 2024
Here is analysis of HA mutations in H5 influenza case in Missouri resident without known contact w animals or raw milk.

TLDR: there is one HA mutation that strongly affects antigenicity, and another that merits some further study.
As background, CDC recently released partial sequence of A/Missouri/121/2024, which is virus from person in Missouri who was infected with H5 influenza.


Here I am analyzing HA protein from this release, GISAID accession EPI_ISL_19413343cdc.gov/bird-flu/spotl…
Sequence covers all of HA except signal peptide, and residues 325-351 (sequential numbering) / 312-335 (H3 numbering). The missing residues encompass HA1-HA2 boundary, and any missed mutations there unlikely to affect antigenicity or receptor binding, but could affect stability.
Read 16 tweets
May 25, 2024
In new study led by @bdadonaite, we measure how all mutations to H5 influenza HA affect four molecular phenotypes relevant to pandemic risk:


Results can inform surveillance of ongoing evolution of H5N1. biorxiv.org/content/10.110…
Image
To measure how all HA mutations affect those phenotypes, we created pseudovirus libraries of HA from WHO clade 2.3.4.4b vaccine strain.

Pseudoviruses encode no genes other than HA, so can only do a single cycle of infection making them safe for biosafety-level-2. Image
First, we measured how all mutations affected HA-mediated cell entry, which is essential for viral fitness

See heatmap below, which is easily visualized interactively at

Some sites constrained (orange); others w many well tolerated mutations (white/blue) dms-vep.org/Flu_H5_America…
Image
Read 15 tweets

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