Bloom Lab Profile picture
13 Jan, 11 tweets, 5 min read
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)
Plot in previous tweet shows E484 mutations often reduce neutralization (lines slope down). Sometimes effect is big (eg, subject C, day 32). But the sera we tested still neutralized E484 viruses, at titers well above those to unmutated virus after 1 dose of Pfizer vaccine. (4/n)
If you recall 2 weeks ago, Twitter was buzzing with people saying "1 vaccine dose is enough, just give that." It puts E484 in perspective to note these mutant viruses still neutralized at a titer greater than what many people were advocating as "good enough" quite recently. (5/n)
Should we worry about E484K & other mutations? Yes! That's why so many of us are working hard to study them. But we need to keep perspective. Reduced neutralization does not mean no immunity, & it will take careful study to determine implications for protection in humans. (6/n)
Finally, results from my lab described above are consistent with work of many other groups. Specifically... (7/n)
@e_andreano @RommieAmaro @McLellan_Lab selected virus w E484K (+ more muts) that was 300-fold more resistant to one human serum. But was still neutralized by that sera & most others they tested, often w titers dropping by just 2-5 fold (Table S1 of biorxiv.org/content/10.110…). (8/n)
@theodora_nyc @PaulBieniasz found E484K reduced neutralization by several human sera, but in all cases sera still neutralized mutant virus, sometimes quite potently (Figure 6C of elifesciences.org/articles/61312). (9/n)
@vsv512 found mutations at E484 often reduced serum neutralization, but every sera they show in Figure S5 of biorxiv.org/content/10.110… still neutralizes the mutants to at least some degree. (10/n)
So we need to monitor these mutations, and be prepared to update vaccines eventually if needed. But we also need to remember that a reduction in neutralization titer, while worrying, is not the same as complete elimination of all immunity. (11/n)

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More from @jbloom_lab

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
2 Dec 20
After posting our pre-print mapping #SARS_CoV_2 mutations that escape Regeneron antibodies, been getting questions about implications for therapies/vaccines. I'd like to contextualize results. Summary is don't be alarmed, but pay attention to viral evolution. Long version: (1/n)
Antibody treatments consist of a single antibody (or in some cases a cocktail of a few) that bind viral spike. Since an antibody binds to one small patch of virus, typically a single mutation is sufficient to escape binding by an antibody. (2/n)
We know from other viruses this can happen. One of the best examples is Regeneron's trial of an antibody to treat RSV in infants (academic.oup.com/cid/advance-ar…). They ran an entire large / expensive clinical trial that failed. Retrospectively, the reason was obvious... (3/n)
Read 21 tweets
1 Dec 20
We mapped all #SARSCoV2 mutations escaping key antibodies used to treat #COVID19 (biorxiv.org/content/10.110…). Surprising observations: one amino-acid mutation escapes *both* antibodies in @Regeneron cocktail & escape mutations selected in infected patient treated w cocktail. (1/8)
Specifically, @tylernstarr, Allie Greaney, Amin Addetia, and @AdamDingens used a deep mutational scanning system to determine all mutations that escape antibodies in REGN-COV2 and LY-CoV016. You can view these complete escape maps here: jbloomlab.github.io/SARS-CoV-2-RBD… (2/8)
Surprisingly, they found a single amino-acid mutation (E406W) can escapes both antibodies in REGN-COV2 cocktail. E406W isn't in structural footprint of either antibody (see image), so mechanism is unclear. But it reduces cocktail neutralization by 100-fold. (3/8) Image
Read 8 tweets
11 Nov 20
I want to flag this important work by @SCOTTeHENSLEY, which is the best study on whether there are pre-existing antibodies to #SARSCoV2 in uninfected people that affect risk of getting #COVID19. (1/7).
Much recent speculation (eg, NY Times by @ginakolata) on if some people have pre-existing antibodies to #SARSCoV2 (eg, from common-cold CoV) that affect risk to get #COVID19. Hensley paper is a well-designed study that *actually answers* this question (2/7)
They looked at sera collected prior to #SARSCoV2. Most sera didn't have antibodies that bound #SARSCoV2 spike, but some had modest binding, mostly to S2 but a few to RBD. None of these sera were potently neutralizing, and no trend for kids to have more of them. (3/7)
Read 14 tweets

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