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1. 2021-01-09 08:21 Robert F. Garry open
   Eaak and Pooh are the ones that worry me the most. I think we're in for a wild ride
2. 2021-01-09 08:36 Andrew Rambaut open
   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.
3. 2021-01-09 08:56 Robert F. Garry open
   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
4. 2021-01-09 09:14 Robert F. Garry open
   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.
5. 2021-01-09 10:11 Kristian G. Andersen
   > 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]
6. 2021-01-09 10:12 Kristian G. Andersen open
   We're talking orders of magnitude difference in binding affinity - that's not nothing....
7. 2021-01-09 10:21 Robert F. Garry open
   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.
8. 2021-01-09 10:23 Kristian G. Andersen open
   Yup - enhances it by quite a bit
9. 2021-01-09 10:29 Robert F. Garry open
   Poor preserved 2/3 predicted O-glycans just like Pooh.

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