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SARS-CoV-2 immune evasion by variant B.1.427/B.1.429
SARS-CoV-2 entry is mediated by the spike (S) glycoprotein which contains the receptor-binding domain (RBD) and the N-terminal domain (NTD) as the two main targets of neutralizing antibodies...
https://www.biorxiv.org/content/10.1101/2021.03.31.437925v1
https://www.biorxiv.org/content/10.1101/2021.03.31.437925v1
The Veesler Lab
@veeslerlab
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Thu Apr 01
The #SARSCoV2 CAL20.C (B.1.427/B.1.429) variant is skyrocketing in California. We describe how it evades the host immune response with @DavideCorti6 @LucaPiccoli9
Led by @Dr_MattMcCallum, Jessica Bassi, Anna De Marco, Alex Chen & @coronalexington
1/7
biorxiv.org/content/10.110…
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The Veesler Lab
@veeslerlab
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Thu Apr 01
The #SARSCoV2 CAL20.C (B.1.427/B.1.429) variant comprises 3 spike mutations: S13I, W152C & L452R reducing plasma neutralizing activity by ~3x and ~5x for vaccine- and infection-elicited antibodies (Abs), compared to the 'ancestral' virus.
2/7 pic.twitter.com/gokFUVb0kg
The Veesler Lab
@veeslerlab
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Thu Apr 01
The neutralization potency of 1/3 of RBD Abs is reduced or abrogated by the L452R spike mutation present in #SARSCoV2 CAL20.C (B.1.427/B.1.429), including clinical-stage antibodies such as Eli Lilly LY-CoV555 (bamlanivimab) & Celltrion CT-P59 (regdanvimab)
3/7 pic.twitter.com/h0VTH4C3ZT
The Veesler Lab
@veeslerlab
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Thu Apr 01
These data concur with deep-mutational scanning data from @tylernstarr @AllieGreaney @AdamDingens & @jbloom_lab
biorxiv.org/content/10.110…
Expert Quote Tweets:
Alex Merz
@Merz
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Thu Apr 01
I'm not a variant-of-concern alarmist. These data from down the hall here in @UWBiochemistry have me concerned. twitter.com/veeslerlab/sta…
Alex Merz
@Merz
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Thu Apr 01
@erik_snapp has thought a lot about viral signal sequences and will want to see this.
Jeremy Kamil
@macroliter
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Thu Apr 01
@Merz @erik_snapp It is “concerning” & easy to have a “HAL 9000” admiration for SARSCoV2 (the most scrutinized case of viral molecular evolution ever— even besting HIV).. but immune responses are polyclonal & the vaccines will still protect u. Thankfully, immune responses are dynamic & polyclonal!
Alex Merz
@Merz
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Thu Apr 01
@macroliter @erik_snapp I'm mainly concerned here about the changes in the signal-adjacent N-domain. I'd certainly not have predicted productive disulfide shuffling.
Fortunately the polyclonal responses to RBD elicited by all extant vaccines still appear robust enough to confer strong protection.
Jeremy Kamil
@macroliter
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Thu Apr 01
@Merz @erik_snapp It is fascinating in the utmost.
David Ridley
@RidleyDM
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Fri Apr 02
@Merz @UWBiochemistry The B.1.429 mutations seem to have radically different effects in different pseudovirus assays; the Balazs lab's work (with dire-seeming results for B.1.351) from a month or two ago didn't show much effect from B.1.429.
medrxiv.org/content/10.110…
Brendan Larsen
@bblarsen1
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Fri Apr 02
This variant also common in Arizona currently and we have sequenced/confirmed on UA campus. twitter.com/veeslerlab/sta…
Dr. Angela Rasmussen
@angie_rasmussen
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Fri Apr 02
For all those wondering how variant mutations can screw up antibody responses, have I got the preprint for you!
Buckle up for a long ride down epistasis & biochem road, thanks to this great study by @Dr_MattMcCallum and colleagues in the @veeslerlab & collabs at @Vir_Biotech. twitter.com/veeslerlab/sta…
Dr. Angela Rasmussen
@angie_rasmussen
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Fri Apr 02
First, some background. All the variants have different constellations of mutations in SARS-CoV-2 spike. This is the protein on the surface of the virus particle (virion) that bind the receptor ACE2 and allow the virus to enter & infect cells.
It looks like this (h/t @profvrr): pic.twitter.com/UJLnBBPJ1w
Dr. Angela Rasmussen
@angie_rasmussen
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Fri Apr 02
As you can see from the above virion, spike is a 3D structure on the surface of the virion. Antibodies bind all over the surface of the spike protein. Some of these bind to important parts of spike that render the virus non-infectious, or neutralize it. pic.twitter.com/i8CHI1eEw1
Dr. Angela Rasmussen
@angie_rasmussen
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Fri Apr 02
We have an enormous repertoire of antibodies that bind specifically to different places (epitopes) on the surface of spike. Each epitope is a unique "lock" that will only fit with a specific antibody "key."
(H/t @dsgoodsell for this gorgeous image. Antibodies=yellow, spike=pink) pic.twitter.com/9MYTCk3CVm
Dr. Angela Rasmussen
@angie_rasmussen
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Fri Apr 02
And to understand how mutations impact this, we need to understand what proteins are. Proteins are encoded by viral genes, and that code contains instructions to assemble a string of amino acids. Long strings of amino acids can fold into different 3D structures, like yarn. pic.twitter.com/fXLzYOSJdH
Dr. Angela Rasmussen
@angie_rasmussen
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Fri Apr 02
Amino acids look like this. They have an amino side (N-terminus) and a carboxyl side (C-terminus). The N-terminus of one amino acid binds the C-terminus of its neighbor to make the chain, or peptide. That bond is called a peptide bond.
en.wikipedia.org/wiki/Peptide_b… pic.twitter.com/ZP3sYmmRoo
Dr. Angela Rasmussen
@angie_rasmussen
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Fri Apr 02
See that R hanging off the carbon in between the N and C termini of the amino acid? That's called a side chain. These are different for each amino acid and can chemically interact with other amino acids to hold the 3D structure together.
(Bear with me, biochem part almost over) pic.twitter.com/XSQ8dUHHkt
Dr. Angela Rasmussen
@angie_rasmussen
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Fri Apr 02
If you liked this part of the thread, Khan Academy has a great explainer of all the different biochemical interactions that can contribute to the 3D shape of proteins.
khanacademy.org/science/biolog…
Dr. Angela Rasmussen
@angie_rasmussen
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Fri Apr 02
If you didn't like this part & didn't want intro to biochem, it's because this is how mutations can influence antibody binding.
A mutation in the genome can change the encoded amino acid, which can change the way amino acids interact, and change the structure of the protein.
Dr. Angela Rasmussen
@angie_rasmussen
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Fri Apr 02
And that's what this preprint is about!!!
Mutations in the B.1.427/B.1.429 variant discovered in California not only change protein structure, but they do so *in combination* with each other.
biorxiv.org/content/10.110…
Dr. Angela Rasmussen
@angie_rasmussen
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Fri Apr 02
This particular variant has 3 spike mutations: S13I, W152C, and L452R. To decode this:
Serine changed to isoleucine at position 13 in the chain
Tryptophan changed to cysteine at position 152
Leucine changed to arginine at position 452
Dr. Angela Rasmussen
@angie_rasmussen
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Fri Apr 02
We already knew that the B.1.429 variant is less effectively neutralized by antibodies in a pseudovirus assay compared to other wild-type (WT) SARS-CoV-2. It resembles the B.1.351 variant first detected in South Africa.
But B.1.429 has different mutations in spike than B.1.351. pic.twitter.com/to4OHmyanZ
Dr. Angela Rasmussen
@angie_rasmussen
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Fri Apr 02
So what's going on here? Well, the L452R mutation is in the receptor binding domain (RBD) of spike. This is the part of spike that binds ACE2 and allows it to get into a cell. ACE2 can't bind the RBD if there's already an antibody there and the virus can't get in. pic.twitter.com/wpFkUajnnS
Dr. Angela Rasmussen
@angie_rasmussen
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Fri Apr 02
And last September, we already had evidence that the L452R mutation resulted in reduced antibody neutralization based on this paper. It showed L452R reduced neutralization by both a panel of monoclonal antibodies & convalescent sera from COVID-19 patients.
cell.com/cell/pdf/S0092… pic.twitter.com/I37XBwzupY
Dr. Angela Rasmussen
@angie_rasmussen
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Fri Apr 02
So that seems pretty straightforward and this paper found similar results. Some antibodies targeting the receptor binding domain didn't neutralize B.1.429 as well as WT virus. Yes, L452R disrupts binding of RBD-specific antibodies. pic.twitter.com/dq3Dfb0p6c
Dr. Angela Rasmussen
@angie_rasmussen
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Fri Apr 02
But what about those other 2 mutations, S13I and W152C? They aren't in the RBD. They are in a different part of spike called the N-terminal domain (NTD). It's at the "front" of the spike protein, pictured here in this structure from @McClellan_Lab.
science.sciencemag.org/content/367/64… pic.twitter.com/1WDJTfV1ga
Dr. Angela Rasmussen
@angie_rasmussen
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Fri Apr 02
Dammit, there's a typo. I meant to tag Dr. Jason @McLellan_Lab!
Dr. Angela Rasmussen
@angie_rasmussen
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Fri Apr 02
Spike on the virion surface is actually a trimer. That means it's 3 individual spike proteins (protomers) put together. The protomers can interact with each other & other proteins (like ACE2 or antibodies) and that can change their shape. This can impact function.
Dr. Angela Rasmussen
@angie_rasmussen
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Fri Apr 02
Spike has several functions besides just binding ACE2 & those functions are conformation-dependent. So antibody binding to other parts of spike besides the RBD (like the NTD) can still be neutralizing if it blocks a critical function.
nature.com/articles/s4139… pic.twitter.com/V0IDpeZ77J
Dr. Angela Rasmussen
@angie_rasmussen
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Fri Apr 02
We know the NTD is important because of studies like this one by @florian_krammer and colleagues. Here it shows that antibodies to the NTD, not the RBD, have reduced neutralization against a variant with mutations in the NTD.
medrxiv.org/content/10.110… pic.twitter.com/cPTnCD6sZc
Dr. Angela Rasmussen
@angie_rasmussen
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Fri Apr 02
And it looks like that's what's happening here too! NTD antibodies completely failed to neutralize this variant. How is that happening? pic.twitter.com/RzzYr5HVDP
Dr. Angela Rasmussen
@angie_rasmussen
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Fri Apr 02
Well, S13I is in a part of the NTD that encodes the signal peptide. Most proteins have these. They are a short stretch of amino acids that tell the protein where to go in the cell, like a barcode used to sort & direct proteins to the nucleus, cell surface, or wherever.
Dr. Angela Rasmussen
@angie_rasmussen
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Fri Apr 02
Signal peptides are clipped off by proteases (enzyme that cuts proteins at a specific amino acid sequence). Most proteases are serine or cysteine proteases, and the "cleavage site" they recognize has either serine or cysteine.
Dr. Angela Rasmussen
@angie_rasmussen
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Fri Apr 02
In the wild-type, that's the serine at position 13. When this is mutated to an isoleucine, it shifts the cleavage site two doors down to the cysteine at position 15.
They used mass spectrometry to confirm that was indeed the case. pic.twitter.com/FcBw9hMgtH
Dr. Angela Rasmussen
@angie_rasmussen
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Fri Apr 02
Okay but this is only a 2 amino acid shift. What's the big deal? Well, serine and cysteine both have another important quality. They both contain sulfur in their side chains, and are the only amino acids that do. They can also form disulfide bonds, where two sulfurs bind together
Dr. Angela Rasmussen
@angie_rasmussen
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Fri Apr 02
Reposting here: I am embarrassed to make such a basic mistake, but I mixed up my AAs. Methionine (not serine) & cysteine are the amino acids with sulfur. I was thinking too much about serine & cysteine proteases and got carried away. Also it's Friday. Forgive me, biochemists!
Dr. Angela Rasmussen
@angie_rasmussen
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Fri Apr 02
And yes, I know methionine can't make disulfide bonds. If it could, it would be...cysteine.
Dr. Angela Rasmussen
@angie_rasmussen
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Fri Apr 02
This is the biochemical equivalent of holding hands. Normally C15 "holds hands" with the cysteine at position 136, and this contributes to the 3D structure of the NTD. But when the signal peptide is cleaved at C15 instead of S13, it's like chopping the C15 hand off.
Dr. Angela Rasmussen
@angie_rasmussen
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Fri Apr 02
However, when W152C is in the mix, there's another cysteine down the road for the C136 hand to hold. That changes the overall 3D conformation of the NTD. Bad news for NTD-specific neutralizing antibodies. pic.twitter.com/wLefvXdrl0
Dr. Angela Rasmussen
@angie_rasmussen
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Fri Apr 02
And here's all that data, confirming that indeed this causes a big old reduction in antibody neutralization, due to the conformational rearrangement of the NTD caused by these two mutations working in tandem. pic.twitter.com/WFSwsUCR7Z
Dr. Angela Rasmussen
@angie_rasmussen
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Fri Apr 02
When individual mutations have a much more profound impact when they occur in combination it's called epistasis.
That's why it's hard to tell what properties the different variants will have just by looking at the sequences and defining the mutations.
Jeanne Marrazzo
@DrJeanneM
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Fri Apr 02
@goepfert_paul @NerdmannID @uabcfar would love your critical thoughts on this interesting discussion of #SARSCoV2 CAL20.C #variant evading host immune response twitter.com/veeslerlab/sta…
Amy Maxmen, PhD
@amymaxmen
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Thu Apr 01
In the lab, coronavirus #variants in California trigger a 3 fold lesser antibody response in serum from people who had been vaccinated.
This study describes why & says this is something to watch. But to be clear, this *doesn't* mean the vaccine is failing. twitter.com/veeslerlab/sta…