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Ok, just to hedge a bit, there is a plausible albeit low likelihood scenario in which the next big wave is driven by a derivative of Omicron. But this exception to the "next big variant comes out of left field" rule would not apply to previous "variants of concern"...
(1/13) https://twitter.com/macroliter/status/1506089264689213441
(1/13) https://twitter.com/macroliter/status/1506089264689213441
This is because unlike previous variants, in which Spike kept getting more & more "open," Omicron evolved a more "closed" Spike, meaning it hides its receptor binding domains from antibodies, just as M.G. Rossman's Canyon Hypothesis would predict. https://pubmed.ncbi.nlm.nih.gov/2670920/ (2/13)
Yes, you could say Omicron's fashion sensibilities take a Victorian-era slant. It definitely has a more chase Spike... (3/n) Image credit: https://commons.wikimedia.org/wiki/File:Magasin_för_konst,_nyheter_och_moder_1844,_illustration_nr_8.jpg
That said, when an Omicron Spike does open one of its 3 receptor binding domains (RBDs) & finds an ACE2 receptor, it latches on much more tightly than previous variants.. you can read more here, h/t @kwan_lab @renegadenarwhal 
https://journals.asm.org/doi/10.1128/mbio.02030-21 (4/13)
https://journals.asm.org/doi/10.1128/mbio.02030-21 (4/13)
But instead of taking the rapid "surface" / "early" entry route where Spike fuses at the plasma membrane, the virus gets in via an slower route, it hitches a ride in a bubble of membrane called an endosome, it takes the "Late entry" route (5/13) https://www.pnas.org/doi/epdf/10.1073/pnas.1608147113
The use of this slower cell entry route has evolutionary implications: because Omicron uses a different structure-function mechanism to hide from antibodies, resembling what "endemic" coronaviruses do, this could influence the trajectory for emergence of future variants.. (6/13)
So, maybe Omicron could mutate enough to drive a new "big wave" simply by escaping a few of the major types of antibody responses that are "broadly" neutralizing? IMO, this is less likely than a new variant out of "left field" but maybe it's not impossible (7/13)
Another important note: @SolidEvidence & collaborators have found evidence in USA wastewater of independently emergent variants with Omicron-like mutations! This means a new variant "out of left field" might still have a more "closed" Spike (8/13) https://www.nature.com/articles/s41467-022-28246-3
These results from @SolidEvidence & friends likely mean that "closed" spikes were on track to evolve in USA & elsewhere-- even if the virus had been magically eliminated from the African continent. The selection pressures for Omicron to evolve led to convergent evolution! (9/13)
Therefore, we *really* don't know what's next in SARS-CoV-2 evolution, other than to say the virus is likely to keep coming up with ways to crack the code and get past our neutralizing antibody defenses (10/13)
But why do I keep emphasizing neutralizing antibodies (nAbs)? Why not "T-cells"? Even though other parts of immunity are important to contain/ limit disease, nAbs are afaik the only surefire way to entirely block infection and hence, prevent transmission...(11/13)
We know that SARS-CoV-2 emerged out of bats already well equipped to broadly mute mammalian interferon responses & limit pro-inflammatory alarm signals long enough to delay recruitment of immune cell "clean up crews," enabling it to efficiently spread from host-to-host (12/13)
So for these reasons, nAbs represent a critical selection pressure on this virus, and for respiratory viruses in general.. so ones that evolve or "come up with" new ways to escape nAbs are going to be hugely rewarded. We will just have to wait to see what happens.. (13/13) END!
