Here's how mutations in #SARSCoV2 Nu variant (B.1.1.529) will affect polyclonal and monoclonal antibodies targeting RBD. These assessments based on deep-mutational scanning experiments; underlying data can be explored interactively at… (1/n)
First, Nu variant has lot of antigenic change. Below are how mutations relate to escape averaged over 36 human antibodies. Many mutations at peak escape sites, especially E484, G446, K417, & Q493. This means even in polyclonal mix, lot of RBD antibodies will be affected. (2/n)
Another way to assess polyclonal escape is how many epitope classes affected (…). We do this using epitope scheme of @bjorkmanlab @cobarnes27 as adopted by @AllieGreaney. In this scheme, three potently neutralizing epitopes: class 1, 2, class 3. (3/n)
Unfortunately, the Nu variant has major escape mutations in each of these three epitope classes, as shown below. (The class 4 epitope less affected, but such antibodies also less potently neutralizing.) (4/n)
Importantly, this does *not* mean Nu variant will fully escape vaccine- or infection-elicited antibodies. @PaulBieniasz @theodora_nyc have shown takes many many mutations to fully escape neutralization (…), & there are also T-cells, non-neut Abs, etc. (5/n)
But I'd expect the Nu variant to cause more of a hit on vaccine- and infection-elicited antibody neutralization than anything we've seen so far. (6/n)
We can also look at some key monoclonal antibodies. the REGEN-COV cocktail is likely to take a hit for the Nu variant, especially the REGN10987 component. (7/n)
The early Eli Lily antibodies like LY-CoV555 (bamlanivimab) and LY-CoV016, which were already in trouble with current variants, aren't going to do any better against the Nu variant. (8/n)
However, it appears the AstraZeneca AZD7442 cocktail and Vir's S309 are likely to hold up better against the Nu variant. See below. (9/n)
You can explore other antibodies that might be of interest to you at…. Importantly, all above results from high-throughput deep mutational scanning, and need to be validated in traditional experiments for high confidence. (10/n)
Also note large antigenic change does not mean Nu will necessarily spread & outcompete other variants. That will also depend on its transmissibility, which has been discussed by @Tuliodna & others (eg, ) and for which data remains preliminary. (11/n)
As @trvrb discussed in excellent recent thread, selection on variants so far may be dominated more by transmissibility than antigenic selection (). But I'm not as sanguine that antigenic selection isn't also playing substantial role... (12/n)
Reason I say that is comparison of Nu variant to BANAL-20-52, a SARS-related CoV isolated from bats. If we compare both BANAL-20-52 and Nu to Wuhan-Hu-1, Nu has *many* more mutations that strongly affect antigenicity (). (13/n)
If selection was mostly for transmissibility, I'd expect sites of divergence of Nu and BANAL-20-52 relative to Wuhan-Hu-1 to perhaps be similarly distributed with respect to antigenic sites. But instead, Nu mutations much more focused in major antigenic sites. (14/n)
We can also use deep mutational scanning to assess how mutations in Nu affect ACE2 affinity (). But I suspect works less well than for antigenic mutations discussed above as there's lot more mutational epistasis for ACE2 affinity (eg, N501 & Q498). (15/n)
Important caveat: all of above is based on deep mutational scanning experiments. I'm sure more Nu-specific data will emerge in coming weeks to months. But I think it's useful to use prospective data we already have to calibrate what to expect. (16/n)
Thanks to @AllieGreaney @tylernstarr for doing deep mutational scanning on which above is predicated, & @NussenzweigL @VUMC_Vaccines @seth_zost @Vir_Biotech for sharing the antibodies. And of course the scientists providing rapid information about Nu ().
And probably I should have used the variant name B.1.1.529 throughout above thread...
For people interested in G446 mutations, I'm going to link back to some details on this site. Here is an old thread discussing how G446 is a major site of escape in the class 3 epitope where (as of March 2021) mutations were not prevalent:
Also, here are old data showing how for a minority of convalescent individuals, the epitope centered on G446 is immunodominant with respect to serum neutralization:
Also, checkout the awesome CoV-RDB database of Bob Shafer, @Philip_Tzou, @sergeilkp, K Tao which compiles experimental data on G446 (and also whatever other mutation you care about):…
Here are data from one of @AllieGreaney's papers (Fig 5 of…) showing that a K417-G446-E484 triple mutant sometimes but not always fully escapes neutralization by RBD-targeted antibodies, and effect is worse for convalescent than mRNA-1273 vaccine sera.
Also adding this as another highly informed view just for balance on question of possible extent of antibody neutralization escape:

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More from @jbloom_lab

21 Nov
I wanted to add to renewed discussion of early Wuhan #SARSCoV2 triggered by @MichaelWorobey's recent perspective (). Although some the Twitter discussion has deteriorated into lab leak vs zoonosis yelling, there's some interesting scientific substance (1/n)
First to clear up point of confusion, there isn't new data about patient zero. As @BallouxFrancois explains (), patient zero was infected probably at least ~1 month before mid-Dec cases @MichaelWorobey is discussing, possibly substantially earlier. (2/n)
Note this misunderstanding about patient zero comes from newspaper headlines, and isn't fault of @MichaelWorobey. In fact, he's done work suggesting patient zero was infected between mid-Oct to mid-Nov (…), although there's still a lot of uncertainty (3/n)
Read 25 tweets
2 Nov
@RolandBakerIII I don't think this paper suggests people were exposed to #SARSCoV2 20 years ago. Rather, it suggests that at a very low frequency some human antibody gene rearrangements will bind strongly to the #SARSCoV2 RBD even in the absence of an immune response selecting for this. (1/n)
@RolandBakerIII This is not terribly surprising. For instance, it's known that even naive humans sometimes have a bit of antibody reactivity to the #SARSCoV2 RBD (see Fig 1B of this paper by @SCOTTeHENSLEY). Indeed, this type of rare low-level naive reactivity...
@RolandBakerIII @SCOTTeHENSLEY is the basis for an immune response, which must start with some binding.

Additionally, these antibodies have genes similar to IGHV3-53, which is known to naturally bind well to the RBD with minimal somatic hypermutation. (3/n)
Read 5 tweets
14 Oct
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)
Read 14 tweets
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

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