In new study, we compared specificity of #SARSCoV2 antibody response elicited by Moderna mRNA-1273 vaccine vs infection. Some interesting differences: vaccine neut activity more RBD targeted, but has broader binding within RBD: biorxiv.org/content/10.110… (1/n)
First @AllieGreaney & Andrea Loes quantified how important RBD-binding antibodies were for neutralization by mRNA-vaccine- and infection-elicited sera. Vaccine sera neutralization was highly RBD directed: >90% of neut by nearly all vaccine sera due to RBD-binding antibodies (2/n)
This result is interesting, as mRNA-1273 encodes entire spike ectodomain with stabilizing 2P mutations. But either those mutations or differences in antigen presentation by mRNA vaccine vs viral infection cause vaccine neut antibodies to focus more heavily on RBD. (3/n)
Note that we performed neuts w lentiviral pseudotype in ACE2-overexpressing cells, which can (over?)-emphasize importance of RBD antibodies for neutralization (nature.com/articles/s4159…). But same assay used for vaccine & convalescent sera, so difference between them is real. (4/n)
Next @AllieGreaney used deep mutational scanning developed w @tylernstarr to map how mutations in RBD affected sera antibody binding. As shown below, vaccine escape maps flatter, especially at early timepoint. Means vaccine sera binding less affected by any single mutation (5/n)
We can look at data other ways. Below is 2D projection of binding-escape from sera & monoclonal Abs in @cobarnes27@bjorkmanlab class scheme. As reported before (biorxiv.org/content/10.110…), convalescent sera dominated by class 2 Abs, but vaccine sera more centered among Abs (6/n)
We can also look at structure. Binding escape from infection-elicited sera heavily dominated by mutations at a few sites such as E484 and F456, and also to some degree in class 3 epitope containing G446. (7/n)
Here is what it looks like for vaccine sera. Sites E484 and F456 are also most prominent binding escape for vaccine sera, but they stand out less than for convalescent sera, again showing vaccine sera antibody binding is more "balanced" across RBD. (8/n)
Finally, we tested key RBD muts in neut assays. As suggested by binding escape maps, single muts caused less dramatic losses in neutralization for vaccine sera.... (9/n)
... For instance, E484K reduced neut by all sera. But for some convalescent sera, E484K eliminated all RBD-directed neutralization. For vaccine sera, it took combined mutations in epitopes of class 1, 2, and 3 Abs to get comparably large decreases. (10/n)
Overall, results indicate there are some differences in specificity of infection- & mRNA-vaccine-elicited antibodies. In particular, vaccine neutralization more RBD-focused, but this probably isn't a bad thing as binding within RBD is broader for vaccine antibodies (11/n)
Why these differences exist is question for biochemists (if due to spike 2P muts) or immunologists (if due to vaccine vs infection response), but will be interesting to understand. Also has implications for viral evolution if mutations affect different sera differently. (12/n)
@AllieGreaney's binding-escape mapping of Moderna vaccine sera is added to our interactive escape map viewer, as well as linked CSV if you want raw data from all studies: jbloomlab.github.io/SARS2_RBD_Ab_e… Here is screenshot of overview plot of relationships among sera & antibodies.
• • •
Missing some Tweet in this thread? You can try to
force a refresh
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