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.

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…

@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

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. 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…

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…

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…
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.

In new study led by @bblarsen1 in collab w @veeslerlab @VUMC_Vaccines we map functional & antigenic landscape of Nipah virus receptor binding protein (RBP)


Results elucidate constraints on RBP function & provide insight re protein’s evolutionary potentialbiorxiv.org/content/10.110… Nipah is bat virus that sporadically infects humans w high (~70%) fatality rate. Has been limited human transmission

Like other paramyxoviruses, Nipah uses two proteins to enter cells: RBP binds receptor & then triggers fusion (F) protein by process that is not fully understood

Over 4 yrs after being first to publicly release SARS-CoV-2 genome, Yong-Zhen Zhang just published large set of viral seqs from first stage of COVID-19 outbreak in China


He uses data to suggest scenarios re early outbreak & root of viral phylogenetic tree academic.oup.com/ve/advance-art…
Zhang recruited nearly all COVID-19 patients hospitalized at Shanghai Public Health Center in first 2/3 (Jan-Sep) of 2020.

The largest source of Shanghai patients in Jan/Feb 2020 was imported cases from Wuhan or elsewhere in Hubei, thereby providing window into Wuhan outbreak.

In new study led by Caleb Carr & @khdcrawford, we measure how all mutation to Lassa virus glycoprotein complex (GPC) affect cell entry & antibody escape

Results show how prospective assessment of effects of mutations can inform design of countermeasures
biorxiv.org/content/10.110… As background, Lassa virus causes of thousands of deaths each year, mostly from spillovers from its rodent host, but there is occasional human-to-human transmission.

Lassa is biosafety-level-4 priority pathogen, & efforts are underway to develop vaccines & antibody therapeutics.

Here is my brief analysis of Dec-28-2019 SARSCoV2 submission to Genbank.

This analysis supports my conclusion to WSJ () that this submission does not tell origin of virus, but does show sequence known to Chinese Academy of Sciences weeks before released wsj.com/politics/natio…
Here is link to my full analysis:

See also images of the same posted below (although it's probably just easier to click on link above and read HTML). github.com/jbloom/SARS2_2…

In new study led by Frances Welsh, we map how mutations to influenza affect neutralization by antibodies from humans of various ages

We find differences in mutation effects among age groups

Virus has evolved especially to escape antibodies of teenagers

biorxiv.org/content/10.110… As background, human influenza constantly evolving. So people exposed to different strains, depending on their age & idiosyncratic history of infection/vaccination.

Different exposure histories cause people to make antibodies w different specificities

rupress.org/jem/article/21…

I wanted to highlight this pre-print by David Ho’s group on the neutralizing antibody response to new (XBB.1.5-based) COVID vaccine booster, as it illustrates some points related to paradigm of updating SARS-CoV-2 vaccines to keep pace w viral evolution.
biorxiv.org/content/10.110… Recall original COVID vaccines worked very well against early SARS-CoV-2 strains

Unfortunately, virus has been evolving, so antibodies elicited by that vaccine don’t neutralize newer viral variants very well

(Other human CoVs also evolve same way: ) journals.plos.org/plospathogens/…

In study led by @bdadonaite we measure how mutations to XBB.1.5 spike affect cell entry, ACE2 binding & serum escape

Two key findings

1⃣ Mutations outside RBD meaningfully affect ACE2 binding

2⃣ Measurements help predict viral clade growth in real worldbiorxiv.org/content/10.110… We made spike pseudovirus deep mutational scanning libraries of mutations across XBB.1.5 spike (as well as XBB.1.5 RBD and BA.2 spike libraries).

We used these libraries to measure how >9,000 mutations affected cell entry, ACE2 binding, and serum antibody escape.

In new work led by Will Hannon, we have created tool for visualizing deep mutational scanning data on protein structures, such as to aid in understanding effects of viral mutations.

Tool is at

Pre-print describing tool: dms-viz.github.io
biorxiv.org/content/10.110… Tool makes it easy to visualize mutation-level measurements for a protein in context of structure. In this thread, I will walk through some examples.

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

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…

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:

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…

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?

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

https://twitter.com/CheeWahTan2/status/1684344961700093953

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.

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…

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

https://twitter.com/jbloom_lab/status/1620571580874080256

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