Private channel session 790
83 messages over 3h 46m, 2021-01-11 – 2021-01-11.
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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Heh - was just talking to Joel and he pointed me to this clip. Listen to the first 45 seconds - you might remember thescene... I admit I always hated this particular scene and thought it was stupid, but now I have to heat my hat and give Butt Lesion some credit...https://www.youtube.com/watch?v=wVri50TXUqU
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Remember that cluster possibly from Uganda with 681R and 613H? Now spreading in UK and has some with 484K. What is happening?
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You tell me - you're the expert
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And I'd add - probably reinfections, possibly asymptomatic driving E484K.
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There's this as well - from Bahia: https://www.preprints.org/manuscript/202101.0132/v1
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@Andrew Rambaut I have to say that if immune selection has driven the appearance of Erik in Amazonia that does make me a bit more worried about the UK dosing strategy.
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Although I guess it also shows that these mutations are going to appear all over the place.
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Great... I guess that's probably separate to the study on Virological. I'm leaning towards E484K being able to escape immunity by now - maybe not in all cases, but at least in some.
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Yes, I think you may be right.
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Are any of you going to be on the WHO call tomorrow focused on this mutation stuff? Wondering if I should go, but itstarts at 3am for me....
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I'm going to have to pass because I have a very late meeting the following night that I'll need to rested for. Looking forward to a debrief from Andrew!
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We have 5 cases of Erik on top of the B117 but they are spontaneous and I doubt driven by antigenic evasion.
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Bum.
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I can't make the WHO thing but they have Tulio, Trevor and Marion on the evolution panel. I couldn't do it so I got Oli instead.
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Really struggling to work out what is going on.
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It seems like all of these lineages are converging to the same set of mutations
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I hope Tulio gets talking combining classification schemes - that will make a fun 7 hours.
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Oli will keep him right
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https://www.fox10phoenix.com/news/fda-to-weigh-half-dosing-moderna-covid-19-vaccines-operation-warp-speed-of ficial-says "These are all reasonable questions to consider and evaluate in clinical trials," the FDA said in a statement on Monday." I agree that the UK dosing strategy is wrong - half dosing makes much more sense with both the prime and the boast. The half and third dosing was already considered in a clinical trial - Moderna's Phase Itrial. Two doses of 10 ug gave essentially the same neut and binding as two doses of 30 ug dose. One dose of 100was terrible and caused al ot more adverse reactions so tjhey stopped it. Hate to be cynical, but I think Moderna isprotecting it's newly hatched golden goose.
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:bomb:
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"It seems like all of these lineages are converging to the same set of mutations." Agree - Spike is covered with glycan - there are only a few places where antibodies can slip in - Eeek and the NTD mutations are in those spots. Once this virus got a furin cleavage site it opened up the possibility for Doug and its 613 twins to destabilzed thetrimers so you could get surface entry. The furin cleavage site is continuing to optimize itself possibly in epistasiswith Doug.
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The Japanese/Manaus cluster has the same nsp6 deletion that the UK and South African lineages have
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Wowser. That's not chance.
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Places where the polymerase has tendency to slip and skip?
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The Manaus/Japanese cluster has a very long branch (too long) - possibly another 'chronic infection' event?
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What does nsp6 do again? Is it possible it's directly interacting with the spike protein to determine e.g., binding?
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```ORF1ab synT733C F681L I760T synC2749T S1188L K1795Q del11288-11296 (3675-3677 SGF) synC12778T synC13860T E5662D spike L18F T20N P26S D138Y R190S K417T E484K N501Y H655Y T1027I ORF3a: C174G ORF8: E92K N: P80R synA28881T synG28882C```
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Bloody hell
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WTF.
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Just bonkers
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Where did they do the AZN trials again?
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Johnson and Johnson in Brazil as well - didn't they suspend it because of mystery illness?
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Yup
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I'm really not sure I believe the chronic theory any more...once may be, but three times? Chronic infections are a tiny fraction of the overall population.
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Epizootic? Chronic infections? Immune escape? I think all in play.
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> It seems like all of these lineages are converging to the same set of mutations And just to this part - it's strongly suggestive of some very pervasive selections pressure that's in common in all these places. Or, alternatively (but I think less likely) something like this: https://www.cell.com/cell/fulltext/S0092-8674(17)30292-1?_returnURL=https%3A%2F%2Fl[...]vier.com%2Fretrieve%2Fpii%2FS0092867417302921%3Fshowall%3Dtrue
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Except that these 3 cases have a shit load of other stuff. Masses of spike mutations (and no synonymous in spike). Orf8 mutations and that nsp6 deletion
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Why're we seeing it now and not earlier? More widespread transmission, vaccines being deployed in some places, more standing immunity. But I do feel something's up here - doesn't seem normal to find so many clearly unrelated lineages ending up with a subset of the same mutations. That's just weird.
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3 very strange events with similar sets of mutations come up.
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Yeah.
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And in different parts of the world - with different climates, so not e.g., a "cold" adaptation.
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Yup. Manaus is not chilly this time of year!
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They DID have a fuck ton of infections in the spring though. Same for UK. Same for RSA.
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Rare chronic infections could just be a ready source of these mutations in combination (because they can all be selected for in the very large population sizes). When you get the combination it takes off
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You just don't get them step by step in normal transmission with bottle necks
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Does Oli/Nuno have any data on reinfections? You mentioned a Virological study yesterday, but not sure if they're looking at that?
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Not yet. Fiacruz has one case of reinfection (not this lineage - but another with 484K)
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Latest UK estimate is a total number of infections as 20% of population.
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Okie dokie - will be important/interesting to know. Also very curious to see what's going to happen in Israel after thevax campaign.
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Manaus estimated at 60-70% from first wave
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Yeah - high... (although I saw quite a number of people disagreeing with that number and the IFR seemed too low tome)
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South Africa high but the area where the variant took off is really high - urban, dense, deprived.
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Yup - seems plausible that immune escape might be the most likely explanation here - whether linked to natural immunity or vaccine induced. Why that would lead to increased transmission, I'm not quite sure I understand - except if e.g., high ACE2 binding is associated with both escape and transmission (not implausible).
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It's all very interesting - although to be honest, I don't need any additional excitement at the moment. I just want toget back to being a totally anonymous scientist (with 323 followers on Twitter) looking at Ebola and Lassa genomes. SARS-CoV-2 is a little too exciting for my liking.
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It could be that the UK one is the only one that is inherently more transmissible (perhaps because of the 681H?).The other two are only taking off in hi-prevalence areas. We will see as more of those arrive in much lowerprevalence areas
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Yup, I talked to Helen Branswell earlier today and I mentioned this exact point too - I'm not sure we have good data suggesting that e.g., the RSA variant is indeed more transmissible (even the data showing it's displacing other lineages is a little lacking - at least what I have seen).
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(No question about the UK lineage though).
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Agree. No comparative rates for RSA. It is just fast growing.
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Although... there is a Finnish import of the RSA variant that has 681H.
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(convergence to the same set of mutations)
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Didn't they mention a couple of months ago that they had a really fast moving lineage that didn't lead to symptoms? I'm wondering if any of that might actually be true - not really "fast" moving, but expanding rapidly and if in a lot ofpeople with previously immunity, maybe leading to less symptoms. That wouldn't be too bad.
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"They" being RSA
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(oh - wait, maybe that was Australia... Somewhere South :wink: )
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So just to conclude to see if I got this right: • One lineage rapidly expanding because it's inherently more transmissible - B.1.1.7. • Several other independent lineages - carrying mutations at 417 and 484 - expanding rapidly in areas of high standing immunity, probably due to escape. Possibly, Nelly is innocent - at least partially and she probably isn't alone responsible for the expansion of both theUK and RSA lineages.
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B.1.1.7 might also have an 'immunity' phenotype in addition to the transmission phenotype. We'll know soon enough.
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And Nelly on its own (in Wales) is not doing that much
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Yup. We have seen Nelly a couple of times in the US too and never associated with increased transmission (although all of that might just be down to chance). It's very plausible that when Nelly is hanging with her friends she might be naughty, but not when she's alone...
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"Nelly is innocent" - we should start a campaign.
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I wanna be sure before we declare her innocent though. Eeek and Pooh though... Fucking bastards.
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Maybe together with Doug and Nelly they're up to no good.
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I think Doug did it...or at least maybe started the process -that is of course after the FCS inserted itself.
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Let's call that initial event Furio
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Furio > Hugo > Doug > Nelly > Eeek, Pooh. I see a pattern emerging.
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Yeah - it's all going to shit...
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I don't think we have any info from previous immunocompromised cases (noros, flu) for such large-scale convergent evolution. Indeed, while I can see immunocompromised cases leading to lots of mutations, lots of the SAME mutations appearing multiple times does smell of very strong and directed selection.
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Just don't know - so much other stuff presumably hitchiking - I just don't think that likely happens via a progressionof individual mutations with bottlenecking transmission.
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We are seeing all these mutations cropping up individually many times. But when they appear in combination now we also get 15 other mutations along side
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I assume there's no recombination involved?
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Also, "immunocompromised" covers a huge range of contexts...
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Can't see anything obvious (recombination)
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But need to keep an eye on that.
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I have been careful not to say immunocompromised - only chronically infected
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The NSP6 deletion is downstream of a crazy T rich region.