Private channel session 1003
36 messages over 3h 25m, 2021-02-20 – 2021-02-20.
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 though is A.23.1 with Doug's neighbour Qeith. It has NSP12 Y346H - related?
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(also 681R of course)
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Full complement is: Spike: F157L, V367F, Q613H, P681R, R102I N: Q39R, S202N NS8: L84S, E92K NSP4: T495I NSP6: L98F, M183I, M86I NSP12: Y346H Could the NSP6 have similar effects to the deletion?
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Much of this is discussed in https://www.medrxiv.org/content/10.1101/2021.02.08.21251393v1.full.pdf but I don't think we mentioned the RdRp mutation because P323L has never really been talked about yet.
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Y346H -not directly in the groove itself *but right in line with the P323*. So putting that charged Histidine in is goingto disrupt the bonding underlaying the channel and have a very similar effect to PhiL. [shared file(s): image.png]
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Bingo.
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So we have a common set of functional sites/effects for all the new variants: An RdRp mutation, an nsp6 modification, spike 613/614, some NTD mutations/deletions and some RBD mutations.
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YES indeed! AS for the nsp6 mutations i'm betting functionally similar to the SGF del -the L98F mutations is probably the most important - in the same "external" loop as the SGF deletion and it makes WF more strongly aromatic. Tryptophans are not kept unless they are needed, so yes affecting regulation of whatever NSP6 is doingto interferon and/or autophagy. Not to dismiss the Met to Inosine mtations that are probably paired and doing something to that TM helix. [shared file(s): image.png]
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Thanks Andrew for the changes to the bat virological! Nicely done and overall much more focused and more importantly *effective* thanks to you and Eddie. @Kristian Andersen the bat-post looking good IMO. Let us know when you're able to take a brief look - life being insanely crazy all around.
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"So we have a common set of functional sites/effects for all the new variants: An RdRp mutation, an nsp6 modification, spike 613/614, some NTD mutations/deletions and some RBD mutations." *Incredible* examples of convergent evolution in real-time. The fact that this emerged in Uganda with not - to my knowledge - a massive number of cases is making me think perhaps that here at least individual adaptation for viral fitness in humans >immune escape. No NellY, EeeK, etc in the A.23.1 Uganda variant, which *may* be the better signs of immune escape *or* fitness plus immune escape.
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Will add ORF8 truncation/modification to that list.
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@Robert Garry There is a cluster of A.23.1 that have Eeek in the UK (which is how I found it in the first place).
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We are writing a paper about the B.1.1.7 variant including its origins and I would love to put some of this speculationin it and then perhaps lay it out in another paper. You interested in being involved? (any of you).
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My current favourite hypothesis is that all of this is about increasing transmissibility in the face of global implementation of NPI which is why we have simultaneous explosive 2nd waves (Doug & Phil) and then the 3rd waves (VOCs). In particular I am wondering if partially-effective measures may have driven evolution for transmissibility in the same way that ineffective vaccines can. Doug & Phil arose in China during the first lock down period (but possibly outside of Wuhan in somewhere like Shanghai) but really took off in Italy. Displacedeverything globally except for areas like Africa where there was not much reported incidence and not much response and lineage A persisted. Then as incidence started to rocket, NPI were implemented and the lineage AVOCs were selected for.
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This would be an explosively political hypothesis given all the anti-lockdown stuff going on.
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I agree with the first part - not sure about the VOCs. I think the selection pressure there is more complicated with RSA/BRA selecting more for evasion, than inherent transmission. The fixation of mutations was probably due tointrahost selection, but I agree the near-fixation in the population likely has more to do with transmission (in apopulation with high levels of immunity - so reinfections).
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B.1.1.7 just looks different to me - again, mutations fixed intrahost in the first place, then near-fixation in the population because of being inherently more transmissible. I think partial immune escape adds to its success aswell.
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But overall, yes, I agree with the hypothesis and think the distinction of different waves being due to differentmitigation efforts is a good one - but as you say, massively politically charged.The fourth wave will likely be driven almost entirely by vaccine escape.
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Makes a lot of sense to me.
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(this ain't the flu, btw). Bob, I'll look at the document today!
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@Kristian Andersen I generally agree - I am 100% convinced that B.1.1.7 is different from everything in its origin story but has converged on the same peak.
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I guess the first question to demonstrate is that has there been a shift in the adaptive landscape (rather than just alot more unusual stuff happening because there are shed loads of cases - although that too). Possible reasons for awide-spread shift in the population level landscapes are 1) NPI, 2) deployment of anti-viral treatments, 3) increasing seroprevalence 4) ? anything else? Then there is the possibility of a shift in within host landscapes - more chronic infections, possibly inimmuno-compromised, possibly treated. Here it is a numbers game - more infections mean more of these and more chance some of them hit this population-fit fitness peak and then transmit onwards.
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Yeah, these are good - I think very likely #1 (broadly defined) and #3 - not sure about #2.
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? anything else? Perhaps something about the demographics shifted too - no data just an impression that a lot more young adults started to get infected in the second wave. That may be because US sucked at testing early on and young adults were getting infected just not counted. Young adults also more likely not to adhere to NPI. In terms ofthe "numbers game" the fact that SubSaharan Africa remains largely devoid of massive outbreaks til you get downto South Africa tells me they are different (which makes the Uganda variant all the more important) - my bias basedon some serology that we are ~sitting on~ trying to get out tells me differences in exposure to seasonal coronaviruses (known and perhaps unknown) could be driving the difference btwn Africa nd the rest of the world.
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Worth adding to the same speculations - what might we expect the future to look like? I have little doubt that the virus will escape our vaccines relatively quickly, meaning we will still continue to see cases - there's no herd immunity here. That scenario may seem like doom, however, it's possible that via vaccination and (re)infections there will beenough immunity to protect against severe disease. I think most virologists believe this is the likely outcome - i.e.,SC2 becomes the common cold. However, I am very concerned this is wishful thinking. SC2 does not appear to be another ccCoV to me. It can infecta huge range of animals and a huge range of tissues. It can infect not just the upper airways (like ccCoVs), but alsolungs, hearts, and other major organs (in fact, pretty much all of them). Some of the reinfections have been severe and have organ involvement (I believe?). To my knowledge, that has never been described with ccCoVs, unless patients have been immunocompromised. So while I'm sure _some_ immunity will _almost_ always be better than none, I am not convinced that this will simply fade into the background like ccCoVs, as I think many scientists believe. It's a very attractive scenario creating a huge confirmation bias. But do we honestly and seriously believe that once most people have gotten that one shot - or been infected - this will become just another ccCoV?I certainly hope so, but I have a hard time convincing myself the data support such a scenario being the most likely outcome.
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> trying to get out tells me differences in exposure to seasonal coronaviruses (known and perhaps unknown) could be driving the difference btwn Africa nd the rest of the world India too. That place is the most mysterious of all to me. _Some_ level of cross-protection would support the notion that SC2 could become just another ccCoV, albeit slightly more severe - but less so than e.g., flu. Dunno.
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Couple of things that are hopeful in terms of whether some sort of "herd" immunity is going to get us out of this mess. 1. Galit's data on OC43 that she showed at last wks conference - prior exposure/existing immunity to OC43basically precluded severe disease. 2. new data showing that a vaccination [one dose] on top of a prior infectioninduces a "massive" and "broad" immune response. 3. exposure to B.1.351 does induce good neuts to .1.351 and 4.the African experience [good point about India], which I think reflects a near universal blanket immunity to"seasonal" CoVs including probably a beta or two we don't yet know about. BUT, I'm the optimistic one.
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I think a scenario of a yearly vaccination with constant updating [stabilized spike of course] is the most likely outcome - and yes it's not the flu so there will a a death toll, so not pretty. Monoclonals (in combo) - again being updated could blunt this. ASnd, some hope for a small molecule drug. Universal CoV vaccine - not so hopeful.
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@Kristian Andersen Yeah - these are not all likely hypotheses I just want to get everything on table.
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Yup, I agree on all of that - with annual updates and us constantly chasing after the virus (which will become easier over time), we'll be fine. My concern is that most people seem to hope for this scenario on "autopilot". Basically, wehave our current vaccines, we'll get them, and it'll be a smooth cruise going forward. I'm not so sure.
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I think I will lay some stuff out there in the B117 paper (which we need to get out quickly because Tulio is being annoying). But then I think a nice piece in Science or Nature to bring it all together?
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Basically - a "what the fuck just happened" piece?
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I think bringing it all together would be really important and helpful to a lot of people - so I'm a yes on that plan.
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Basically fleshing out a little more _many_ of the points already made in this thread. Maybe we can deploy some AIto scan through our text and write the paper for us...
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Is that what you refer to your grad students as?
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"Eddie Holmes", actually - but close.