This new #SARSCoV2 Omicron subvariant (BA.2.75) flagged here by @PeacockFlu is worth tracking, as it has appreciable antigenic change relative to its parent BA.2. Key mutations: G446S & R493Q
Here is summary of what those mutations imply for antibody escape & ACE2 affinity (1/n)
. Therefore, BA.2.75's antigenic advantage relative to BA.2 will be most pronounced in people who have NOT had BA.1 exposure. (3/n)
For comparison, BA.4/5 has ~3-fold drop in neutralization relative to BA.2. Our antibody-escape calculator (academic.oup.com/ve/article/8/1…), suggests BA.2.75 will have similar drop in people w/o BA.1 breakthrough infection, but less of a drop in people w prior BA.1 infection (4/n)
The difference is because BA.4/5 have F486V mutation (which escapes antibodies from both current vaccine & BA.1 breakthrough), whereas BA.2.75 lacks F486V but has G446S (which escapes antibodies from current vaccine but less so from BA.1 breakthrough). (5/n)
There is also an evolutionary role for R493Q, which is in both BA.2.75 & BA.4/5. This mutation is reversion of Q493R that occurred earlier in BA.2's evolution. R493Q is NOT a major antigenic mutation, but enables both F486V (in BA.4/5) and G446S (in BA.2.75). (6/n)
) shows both G446S & F486V decrease ACE2 affinity of BA.2 (by -0.1 & -0.5 log10 Kd, respectively). But R493Q buffers these mutations by increasing ACE2 affinity by 1.1 log10 Kd. (7/n)
In general, ACE2-affinity enhancing mutations like R493Q (and previously N501Y) are often found with antibody-escape mutations because they buffer the cost of affinity-decreasing escape mutations:
Note my above analysis only relates to antibody escape. Success of any variant also depends on inherent transmissibility, which is hard to measure experimentally & can only be estimated once there is sufficient epidemiological data to see how it fares in human population (9/n)
But based on limited info so far, I agree with @PeacockFlu that BA.2.75 is worth monitoring. It will have antibody escape that is similar to that for BA.4/5 with respect to current vaccine (hopefully those Omicron vaccine updates are coming soon...) (10/n)
Also, see this thread (& associated paper) by @jianfcpku describing work w @yunlong_cao, Sunney Xie, et al that provides most of deep mutational scanning data on which my above analysis is based, and also highlights importance of site 446:
Finally we should be glad that G446S in BA.2.75 is not on BA.4/5 background w F486V. Most concerning antigenic variant would have mutation at site 486 plus one at site like 346, 444, or 446 (
In our deep mutational scanning of BA.2 RBD, N460K increases both ACE2 affinity (+0.2 log10 Kd) & RBD expression (a proxy for stability). See jbloomlab.github.io/SARS-CoV-2-RBD…
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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
RBP forms tetramer in which 4 constituent monomers (which are all identical in sequence) adopt 3 distinct conformations
RBP binds to two receptors, EFNB2 & EFNB3
RBP’s affinity for EFNB2 is very high (~0.1 nM, over an order of magnitude higher than SARSCoV2’s affinity for ACE2)
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
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.
Overall, Zhang obtained 343 near-full-length SARS-CoV-2 sequences from 226 distinct patients, including 133 sequences from samples collected no later than Feb-15-2020.
A phylogenetic tree showing these sequences is below.
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.
We used pseudovirus deep mutational scanning to study effects of nearly all 9,820 amino-acid mutations to Lassa’s GPC at biosafety-level-2 by making genotype-phenotype linked libraries of lentiviral pseudotypes blog.addgene.org/viral-vectors-…
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…
I also don't think Genbank/NCBI could have reasonably known at time that this sequence was so valuable given that Chinese govt did not announce they had sequence or had submitted it, and Genbank receives vast numbers of submissions.
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
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