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Bloom Lab Profile picture
@jbloom_lab
Oct 8, 2024 • 10 tweets • 3 min read • Read on X
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
One of the California human cases also has A218S (a la A214S or A230S). This mutation appears to be unique to this case.
Based on our deep mutational scanning, none of these mutations have an obvious strong effect on HA antigenicity or receptor usage ()

(As always, caveat is that there could be some effect we are missing.)dms-vep.org/Flu_H5_America…
Here are the locations of the mutations on the HA structure. Two are on the head, one is in the stalk. Image
The California human cases *lack* the A160T (a la A156T or A172T) mutation that was present in a recent human case from Missouri and is known to cause a substantial antigenic change.
Note above thread only discusses HA mutations, not mutations in other parts of genome which could be relevant.

Also, HA mutations could have some important effect I am missing (see for more discussion)

But I see nothing in HA mutations of obvious alarm
Here is link to interactive HA structure where you can look at mutations and associated deep mutational scanning data: dms-viz.github.io/v0/?data=https…
I apologize for typo here, it is S323N in H3 numbering, not S336N. The table attached to the above post is correct.

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More from @jbloom_lab

Bloom Lab Profile picture
May 27
In new study led by @timcyuu, we measure how mutations to H3 flu HA affect cell entry, stability & antibody escape

We find pleiotropic effects of mutations on these phenotypes shape evolution: epistasis alleviates cell-entry but not stability constraints

biorxiv.org/content/10.110…
We used pseudovirus deep mutational scanning to characterize all mutations to a recent H3N2 HA. This approach uses virions that can only undergo one round of cell entry & so are not pathogens capable of causing disease.

All measurements available here: dms-vep.org/Flu_H3_Massach…
As can be seen below, constraint due to mutational impacts on cell entry are widely distributed across HA including receptor-binding pocket and fusion peptide. But mutational constraint due to HA stability is concentrated at trimer and HA1-HA2 interface. Image
Read 8 tweets
Bloom Lab Profile picture
Mar 12
In study led by Cassie Simonich & T McMahon, we quantify antigenic evolution of RSV F. Important because:

1⃣ RSV top cause of infant hospitalization in USA

2⃣ New antibodies & vax can prevent hospitalizations

3⃣ But will virus evolution erode efficacy?

biorxiv.org/content/10.110…
RSV has high burden in infants: top cause of infant hospitalization in USA, 2nd-leading cause of infant mortality globally

A monoclonal antibody (nirsevimab) recently recommended for infants born in USA in RSV season. It prevents hospitalizations

pubmed.ncbi.nlm.nih.gov/38457312/
RSV vaccines also now approved to protect infants (via maternal vaccination) & elderly

But some viruses evolve to erode antibodies and vaccines

Will RSV do same? Worryingly, a Regeneron antibody failed phase 3 trials due to resistance in some RSV strains
pubmed.ncbi.nlm.nih.gov/32897368/
Read 11 tweets
Bloom Lab Profile picture
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
Bloom Lab Profile picture
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
Bloom Lab Profile picture
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
Bloom Lab Profile picture
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

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