Private channel session 783
34 messages over 4h 33m, 2021-01-09 – 2021-01-09.
A “conversation” here is an activity session — a run of messages with under 60 minutes of silence inside it. The channel had no native conversation boundaries.
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Interesting (from Hopkins -sidenote daughter whose finishing up her doctorate there just got the second dose of Phizer - fever muscle aches not pleasant).
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Just a reminder [to self] that in terms of Eeek and Pooh :clap: E484K is very likely a product of immune escape atsome point in the transmission chain - one if if not the dominant neutralizing epitope. It does not appear to interact with ACE2 directly [but all protein structures are models and all models are wrong]. Pooh - deserves a second:wave: round - appears to be an upgrade at the FCS. As the paper cited below summarizes the FCS is actually influenced alot by the flanking residues on either side. H being a positive charge in the P5 position is an upgrade to the furin site from P. https://journals.sagepub.com/doi/full/10.4137/BCI.S2049
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Also worth noting that the upstream residues QTQTN that Andrew et al and others have shown are often deleted in cell culture (SC2 doesn't need a FCS in culture apparently) are pretty much a PERFECT upstream context sequence for optimal FCS cleavage being small and hydrophilic amino acids. @Kristian Andersen maybe Karthik could look but I think this deletion or something like it showed up as a minor species showed up in the Vero passage that Brandon did. QTQTN is present in GD pangolin and RaTG13, but not SC1.
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We have also seen an odd import (possibly from Uganda - but quite possibly with an intermediate location) that hasP681R so making the FCS RRRK - any thoughts on that? Interestingly it also has V367F & Q613H (but not614G - it is in lineage A). A small cluster, possibly growing.
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Interesting - P681R would make the FCS RRRAR right? which is predicted to be a much better site than PRRAR but not as good as RRAR/KR. Q613H is pretty analogous to the lion mutation (from my virological christmas card) Q613R, both to a positive charge at pH >6.
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There are lions in Uganda.
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(so I have heard - I was supposed to be going there last year, sigh)
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Ahhh yes - the Queen Victoria hotel is pretty special and you can take a side trip to the Ziika forest. Curious about Pooh, showing up in NIgeria (Christian Happi) and now Poor in Uganda. Not that many sequences from Africa, Something usual in Africans going on which I suspect relates to prior exposure to some yet uncharacterizedbetacornaviruses.
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Lot of immunosuppressed Africans, HIV and other causes, as well. So having the P681 changes may fit that meme.
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This is the new USA cluster with Eeek and Pooh: [shared file(s): image.png]
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All in Maryland? Worth keeping an eye on it for sure...
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This one only has 484K but spans 4 months and 4 states: [shared file(s): image.png]
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@Robert Garry Perhaps it was around the Capitol on Tuesday
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@Robert Garry That would be ironic if that likely super-spreader event spreads a new "super" variant.
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Eaak and Pooh are the ones that worry me the most. I think we're in for a wild ride
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I am trying to decide if this is a 'phase-change' in the evolution of the virus (i.e., driven by standing immunity) or is itjust that now there are simple enough cases that these combinations (of previously individual mutations) are startingto appear together and so the synergies are apparent.
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I would not rule out that some of the Pooh-related mutations are immune driven as well - some of the christmas card mutations near the FCS could well be epitopes.https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0238089
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I wouldn't rule-out a phase change. The UK and ZA variants feel like some nonlinear processes occurring. Epistasisis a real thing. Did Doug somehow open the floodgates enabling Nelly, Eeek and Pooh and multiple combinations?On the "up" side it seems to me that at least that a pattern of hotspots for mutations (Xmas card) are starting toemerge. New sampling of the combos as you document above does seem like an ongoing and perhaps acceleratingprocess. Looking ahead I worry about the fertile ground of Africa which has been largely spared being more susceptible to a Phase II variant.
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> I am trying to decide if this is a 'phase-change' in the evolution of the virus (i.e., driven by standing immunity)I have been wondering about this myself - definitely feels like it. The areas where we have seen these popping uphave had a lot of COVID-19 going around, so a fair bit of standing immunity. I absolutely hope not though - it's apretty scary thought and I have no idea how driving vaccines into a raging pandemic will change that landscape.> Pooh - love it :wink:. Bob, how does the RRRAR affect the predicted O-Glyc? Presumably knock out one of the predicted sites? And just to get back to a question we talked about a couple of days ago - (a) might E484K just be overall better atevading immunity or is it just that it (b) changes an important epitope? I have been thinking about this a lot... I had been leaning towards the former, but now I'm getting increasingly concerned it's the latter. Mostly based on this paper: https://www.biorxiv.org/content/10.1101/2021.01.06.425392v2.full.pdf. Is it possible that the combo of Doug, Eeek, and Nelly simply leads to a virus that have such a high affinity for ACE2 that the spike-ACE2 interaction more effectively outcompetes spike-NAb binding? Not inconceivable - I mean, take a look at the difference in binding affinity here: [shared file(s): Screen Shot 2021-01-09 at 10.01.04 AM.png]
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We're talking orders of magnitude difference in binding affinity - that's not nothing....
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Looks like Eeek even though it doesn't seem to contact ACE2 nevertheless can enhance binding when coupled with Nelly. Surprising but perhaps not shocking.
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Yup - enhances it by quite a bit
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Poor preserved 2/3 predicted O-glycans just like Pooh.
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Immune escape plus enhanced fitness is ......worrisome.
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That's to put it mildly...
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Also, this is basically the final confirmation that @Andrew Rambaut was absolutely correct in ringing the big redalarm bell:https://twitter.com/LindorffLarsen/status/1347916349704646656?s=20Looks like the doubling rate might be a little less in DK than UK, but clearly same trajectory.
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And I have mentioned this several times, but worth repeating - it's unclear to me we'll be able to control COVID inthe US in a couple of months. Just too much inaction and lack of coordination, coupled with pandemic fatigue. Iwould not be surprised if we reach 1m fatalities by summer.I hope I'm wrong. Very wrong.
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False reports of a new 'U.S. variant' originated from Dr. Deborah Birx on the task force.
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Birx needs to retire - I got into more than one scientific disagreement with her back in the day on AIDS study sections - doesn't really think things thru - overtly political - perfect for trump, but hopefully we do better going forward.
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"it's unclear to me we'll be able to control COVID in the US in a couple of months." Actually no way. The only thing that is going to stop this in the US is vaccine for the reasons you mention. One has to hope that despite the variants the vaccines retain enough efficacy to blunt the spread [i'm hopeful but not convinced] and that somehow all stopspulled out they can be manufactured in sufficient quantity and distributed to enough people who agree to bevaccinated. It's going to be more than a few months before case numbers come down to "control" in the best case. Need to start on v2.0 of the vaccines right now.
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The vaccines are not going to be distributed in time - not by a long shot
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Here's a very simple analysis illustrating the issue - we're currently Rt ~1 [shared file(s): SEIR.jpg]
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[this is for San Diego - ~ 1% current frequency].
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Yes - totally - the new variants or if ET is correct strains are coming just like in the UK. And I agree they are going todominate before the vaccines will even start to have any effect on spread.