We have completely mapped #SARS_CoV_2 mutations that escape binding by LY-CoV555 (antibody that forms the basis for Eli Lilly's bamlanivimab) both alone & in cocktail with LY-CoV016 in a new study led by @tylernstarr w/ @AllieGreaney & @AdamDingens: biorxiv.org/content/10.110… (1/n)
We corroborate recent work showing LY-CoV555 and its cocktail with LY-CoV016 is escaped by mutations in B.1.351 and P.1 viral lineages (E484K and K417N/T, respectively), and also show that LY-CoV555 is affected by the L452R mutation in B.1.429. (2/n)
Specifically, we used complete mapping approach we had previously applied to antibodies in REGN-COV2 (science.sciencemag.org/content/371/65…) to also determine how all RBD mutations affect LY-CoV555 binding. Below are maps of how mutations affect binding (big letter = escape from binding) (3/n)
Consistent w recent work by Wang et al (David Ho's group, biorxiv.org/content/10.110…), E484K escapes LY-CoV555 and K417N escapes LY-CoV016, which means cocktail won't work against B.1.351. Also, we show L452R affects LY-CoV555 binding. (4/n)
More generally, our maps enable prospective surveillance of other mutations that affect binding by these antibodies. Here are maps of mutations that affect binding by each (y-axis) versus current frequency in sequenced isolates (x-axis). (5/n)
You can interactively explore our escape maps and download raw data here: jbloomlab.github.io/SARS-CoV-2-RBD… (6/n)
Finally, our results and other recent work in this area strongly suggest a priority should be to diversify epitopes targeted by antibodies in clinical development, such that the same mutations selected under immune pressure don't also escape so many clinical antibodies. (7/n)

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More from @jbloom_lab

9 Feb
Our complete mapping of mutations to #SARSCoV2 RBD that reduce binding by convalescent human plasma is out in @cellhostmicrobe (cell.com/cell-host-micr…). Right now E484K getting lot of attention, but I want to emphasize what our results suggest to keep eyes on in *future* (1/n)
To recap, we measured how all mutations to RBD reduce binding by antibodies in convalescent plasma. Lots of person-to-person variation in effects of mutations, but mutations at E484 have biggest effect. My old summary from early Jan: (2/n)
That summary was written just as E484K-containing 501Y.V2 (B.1.351) & 501Y.V3 (P.1) lineages were being reported & focused on E484 as most important site of mutations. Since then, many labs have characterized these lineages to confirm E484K is major antigenic change. (3/n)
Read 7 tweets
25 Jan
Our study mapping #SARSCoV2 mutations that escape key therapeutic monoclonal antibodies is out in @ScienceMagazine. The study also shows that some of these escape mutations arise in a persistently infected patient treated with REGN-CoV-2: science.sciencemag.org/content/early/… (1/n)
I previously summarized the pre-print (), so in this thread I'll just update on new insights since we posted the pre-print in late November. (2/n)
In the study, we mapped all mutations to #SARSCoV2 RBD that escape binding by recombinant forms of antibodies in REGN-CoV2 cocktail (Regeneron) and LY-CoV016 antibody (Eli Lilly). These maps are useful because some of these mutations are appearing in new viral lineages (3/n).
Read 10 tweets
13 Jan
In this short thread, I am going to plot some experimental data in a way that provides perspective on concerns that #SARSCoV2 mutation E484K will completely abolish immunity. (Thanks @profshanecrotty @apoorva_nyc for inspiring this post.) (1/n)
Last week, we posted a study describing how some #SARSCoV2 mutations, especially at site E484, reduce binding & neutralization (). This study (& similar ones by other) have drawn a lot of interest since E484K is in B.1.351 viral lineage. (2/n)
However, E484 mutations *reduced* neutralization, they did not ablate it. The plot below shows how E484 reduces neutralization titers for 16 sera. The dashed orange line shows titers against unmutated virus (measured by Pfizer) after 1 dose of BNTB162 vaccine. (3/n)
Read 11 tweets
5 Jan
Here's plot of how mutating RBD sites affects average serum binding (y-axis) vs frequency of mutations (x-axis). E484K in S African lineage most worrying. But others affect some serum to various degrees & no such thing as "average" human when it comes to serum specificity (13/n) Image
Importantly, we only looked at RBD muts, since majority of neut activity of most sera from RBD antibodies (2nd tweet of thread). But NTD muts also important; see @10queues @mccarthy_kr @GuptaR_lab @e_andreano @McLellan_Lab: biorxiv.org/content/10.110…, medrxiv.org/content/10.110… (14/n)
This relative role of RBD & NTD mutations consistent w historical evolution of common-cold CoV-229E, where mutations concentrated in receptor-binding loops of RBD, but also in parts of NTD. Here is plot of mutational variability in CoV-229E spike: (15/n)
Read 16 tweets
5 Jan
We mapped how all mutations to #SARSCoV2 receptor-binding domain (RBD) affect recognition by convalescent polyclonal human sera (biorxiv.org/content/10.110…).

Among implications: E484K (South African lineage) worrying for immune escape; RBD mutations in UK lineage less so (1/n).
We first determined where in #SARSCoV2 mutations most affect viral neutralization. @veeslerlab had reported RBD-binding antibodies responsible for most neut activity of human sera: sciencedirect.com/science/articl…. We validated w sera from @HelenChuMD's HAARVI cohort (below) (2/n)
Since RBD is main antigenic region (although NTD also important, see below), @AllieGreaney applied method she & @tylernstarr developed for monoclonal antibodies (sciencedirect.com/science/articl…) to map how all mutations to RBD affect binding by *polyclonal* human sera (3/n)
Read 28 tweets
18 Dec 20
In new work, we show a human coronavirus evolves to escape neutralization by antibody immunity (biorxiv.org/content/10.110…). Specifically, we studied the historical evolution of the common-cold CoV-229E to learn how #SARSCoV2 might evolve & if we might need to update vaccines. (1/n)
We first built a phylogenetic tree of CoV-229E evolution from 1984 to the present, and experimentally reconstructed the spike from viruses at 8 year intervals (1984, 1992, etc; see large black strain names in tree below). (2/n) Image
Next we tested how well human sera collected shortly after 1984 neutralized each viral spike. Below is serum from 26 yr old collected in 1985: it neutralizes 1984 virus well, but 10-fold less activity against 1992 virus & no activity against viruses after 2008. (3/n) Image
Read 17 tweets

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