In a new study led by @AllieGreaney, we show that infection with a #SARSCoV2 variant elicits an antibody response with somewhat shifted specificity relative to early Wuhan-Hu-1-like viruses that were circulating early in the pandemic:… (1/n)
It's now known that #SARSCoV2 variants have mutations that reduce neutralization by antibodies elicited by early viruses, which are source of spike in current vaccines. This figure from @VirusesImmunity shows neutralization drops for common variants: (2/n)
But do the antibodies elicited by infection with these variants have different specificities, such that humoral immunity from infection with variants will be differentially affected by specific mutations? (3/n)
To investigate this, we worked w @sigallab @Sandile_Cele22 @farinakarim @khadijakhan24 at @AHRI_News to look at antibodies elicited by B.1.351 variant (ie, Beta). This variant has mutations that reduce neutralization by antibodies elicited by early viruses & vaccines. (4/n)
Importantly, prior work by @sigallab @Tuliodna & Penny Moore already suggests B.1.351 elicits somewhat different specificities, as antibodies from B1.351 neutralize early #SARSCoV2 better than vice versa:… &… (5/n)
To investigate specificities at higher resolution, we first examined what part of virus targeted by neutralizing antibodies elicited by early 2020 #SARSCoV2 & B.1.351. Both elicited neut activity dominated by anti-RBD antibodies, especially B.1.351. (6/n)
@AllieGreaney then used deep mutational scanning developed w @tylernstarr to see where in RBD antibodies elicited by variants bind.

We can divide RBD in 4 major epitopes using scheme of @cobarnes27 @bjorkmanlab: B.1.351 has antigenic mutations in class 1 & 2 epitopes (7/n)
Our results show that antibodies elicited by B.1.351 are notably more skewed to class 3 epitope, although they still target class 2 epitope quite a bit. (8/n)
These differences also hold up in neutralization assays. For instance, mutations at class 2 epitope sites like 484 can dramatically decrease RBD-directed neutralizing activity of serum antibodies from early #SARSCoV2, but cause much milder drops for B.1.351 elicited sera. (9/n)
So what does all this mean? At a very specific level, perhaps not much: as @trvrb has noted (), other variants including B.1.351 have largely been outcompeted by Delta.

But we think the *principle* will hold more broadly. (10/n)
RBD mutations in B.1.351 are also showing up in some Delta variants, and more generally the virus will continue to evolve. As it does so, keep in mind that this evolution will shift which sites are immunodominant, and so which mutations have the largest antigenic effects. (11/n)
Therefore, it will be important to keep in mind that our understanding of the "antigenic structure" of the #SARSCoV2 spike might need to continually be assessed as immunodominance hierarchies start to shift. (12/n)
Thanks to our collaborators; in addition to ones already mentioned: @HelenChuMD @veeslerlab @DavideCorti6 @eguia_rachel A Loes, @johnbowenbio, J Logue.

Finally, all our antibody & sera deep mutational scanning available for viewing & download at… (13/n)

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More from @jbloom_lab

7 Oct
To answer below question, most bat CoV don't bind human ACE2 strongly, but can happen incidentally in evolution. Presumably because some mutations that increase binding to bat ACE2s incidentally increase binding to human ACE2, which has substantial homology to bat ACE2s. (1/6)
One example is recently described BANAL-20-52 bat CoV, which binds human ACE2 strongly (…). Another is SHC014 (…), which @TheMenacheryLab @Baric_Lab showed infects human cells despite having evolved in bats. (2/6)
More broadly, we recently did large yeast-display survey of SARS-related CoV RBDs and found that some bind human ACE2 (and some ACE2s from other species) well despite being from bats (…). (3/6)
Read 6 tweets
21 Sep
For anyone who doesn't want to do alignments, here are spike amino-acid mutations separating #SARSCoV2 from newly discovered bat CoV BANAL-20-52, which is #SARSCoV2's closest known relative in spike.

Mutations as #SARSCoV2 Wuhan-Hu-1 to BANAL-20-52 in #SARSCoV2 numbering. (1/6)
There are 16 amino-acid substitutions across the 1273-residue spike.

In addition, there is an indel at the furin cleavage site, since like all other known bat sarbecoviruses, BANAL-20-52 lacks the furin cleavage site found in #SARSCoV2. (2/6)
For comparison, Beta and Delta #SARSCoV2 variants each have 7 amino-acid substitutions relative to Wuhan-Hu-1.

So BANAL-20-52 spike about twice as diverged as current #SARSCoV2 variants are from early #SARSCoV2, *plus* of course BANAL-20-52 lacks the furin cleavage site (3/6)
Read 7 tweets
13 Sep
This is a really good and thoughtful thread by @stuartjdneil! It's great to see these clear explanations and chains of reasoning that more and more virologists are posting about the topic of risk-benefit of certain experiments. (1/3)
I had posted some of my own thoughts here (), and other virologists like @wanderer_jasnah @stgoldst have made excellent points in various comments and replies. (2/3)
It's clear we all agree that most virology experiments are valuable & safe with current biosafety rules.

Then there is a small slice of experiments that most agree are too risky.

Finally, there is a gray area that requires nuanced weighing of risks and benefits. (3/4)
Read 4 tweets
11 Sep
Hi @angie_rasmussen, thanks for asking these important questions about risk / benefits of different types of virology experiments. Because you locked your Tweet thread, I can't reply, so will post my thoughts here in a new thread that anyone can reply to. 🧵
This is not about being pro- or anti-chimeric virus, but about risks of specific experiments. As scientists we have this responsibility. My favorite essay is Feynman's The Value of Science (…), which he wrote after his field of physics built nuclear bomb.
As we all know, experiments that manipulate viruses have yielded important scientific insights & been of tremendous value to human health. This includes smallpox vaccine, oncolytic viruses, gene delivery, etc. Even some vaccines (eg, J&J #SARSCoV2 vaccine) are chimeric viruses!
Read 23 tweets
1 Sep
@zeynep, here are some more interesting early #SARSCov2 dates for you. Check out the description of the samples in the final published version of this paper (…): "Eight COVID-19 pneumonia samples were collected from hospitals in Wuhan in January 2020." (1/3)
See if you can spot difference in how same samples are described in PubMed Central version (…), which would have been built from original peer-reviewed manuscript: "Eight COVID-19 were collected from hospitals in Wuhan from December 18 to 29, 2019." (2/3)
Journal early access version of manuscript, which would have been the peer-reviewed version, also says samples from December 18-29, 2019 (…). There is no correction in journal, so presumably dates changed at post-peer review manuscript proofing stage. (3/3)
Read 7 tweets
26 Aug
Interesting study suggests one of the mutations that distinguishes two early lineages (A & B) of #SARSCoV2 in Wuhan has functional effect. Here's my summary of evolutionary relevance of this pre-print by @Digs66768072 @nisha_kriplani @dr_sara_c… 👇🧵
Early #SARSCoV2 from sequences Dec-2019 and Jan-2020 are all closely related as expected in new outbreak. But there is some genetic variation. One classification system (proposed by @arambaut et al) divides early #SARSCoV2 sequences into lineages A and B (…)
Lineage A is closer to bat coronaviruses, and so is probably more similar to first virus that entered humans. Lineage B has two mutations that make it more different from bat coronaviruses (T8782C & C28144T), and so probably descends from lineage A. As paper above says: Image
Read 9 tweets

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