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Before we get into this post, we need to flag a major caveat: that the Covid variant that will be the major focus of this piece, B.1.640, looks as if it could largely or entirely escape the current vaccines because it is very different from wild type and Delta. Our GM was telling our Covid brain trust about this variant when it hadn’t even been given a designation, in late October, after it had been sequenced in Africa. It has started spreading and a case was sequenced in California.
However, let us stress that how serious this variant is, or if it in the end even rates as serious, is not yet known.
But what is disturbing is the failure of the press, even the scientifically-oriented press, to say much about variants. The charitable interpretation is that like so much other Covid-related messaging, no one want to spook the horses until they are sure some new potentially bad development really is bad
But requiring that level of proof is what let Covid become a pandemic in the first place. I don’t know how many of you recall February 2020 well, but there were plenty of sites, as well as officials, dismissing concern about Covid and the Trump plan to shut down air travel as wildly exaggerated to stoke xenophobic China-bashing. Remember Pelosi showing her solidarity with Covid by going to Chinatown for a meal?
And even though scientists are looking at sequencing data from countries around the world, it’s not clear how many of the misbehaving blips on their radars are being reported to public health officials, let alone doctors who are too busy treating patients to keep up on bleeding edge concerns. GM explains that how we do science is part of the problem:
There are large collaborations and whole labs that do things like following variants; the problem is that by the nature of the scientific process contrasted with the nature of the process of viral spread, one cannot wait for them to understand what is happening. So one has to look into the databases in real time and exchange information with other people who do the same.
But another very real issue is that governments ex China have thrown in their lot with prioritizing business over public health. So they aren’t about to give the Confidence Fairy fainting spells by giving warnings about variant risk and spread, particularly since by the time it shows up in sequencing, an unknown number of people in the vicinity of the infected are almost certain to have been exposed.
GM gave this high-level overview yesterday:
The most likely future major developments of the pandemic fall into one of these three scenarios:
1. We get a second-generation Delta variant that has a major advantage over all other Delta lineages. This is the most likely one simply because right now 98% of the virus circulating around the world is Delta and Delta was the most fit variant to begin with.
2. We get a second-generation variant from one of the lineages that have still survived the Delta sweep that is capable of competing against Delta. Eyes are on Lambda/C.37 and Mu/B.1.621 and possibly P.1, because those are the only first-generation variants that still circulate in significant numbers in South America
3. Something new appears out of nowhere that is fitter than the rest. This will most likely come from Africa– there is no surveillance in the depths of the continent and there is no knowing what is brewing there.
Note, however, that there should be no expectation of another Delta-like sweep, i.e. something so much fitter than everything else that it displaces (almost) all other variants. Those may well be very rare events, it’s just that there an easily accessible peak in the fitness landscape in this case. We can end up with a zoo of variants of roughly comparable fitness. Which will be worse than having a single dominant one, as then vaccines will have to target all of them, while immunity from infection with one will not work well against the others.
B.1.640, if it turns out to be a significant event, and not just something we are way too concerned about for no reason, is exactly a #3 kind of event. So was C.1.2 (which has not gone anywhere either, it is in fact still slowly gaining ground in South Africa)….
But in general, we have learned a lesson from the last year — single mutations on currently fit backgrounds rarely make a big difference. On many occasions — E484K on top of B.1.1.7, K417N on top of B.1.617.2 (the original Delta+), etc. — we got very worried about such variants, but they went nowhere.
The real breakthroughs come when multiple mutations combine in the right way to make something distinct and highly fit. And usually that happens unobserved, quite often in the same individual with a chronic infection, and then it bursts on the scene as a newly formed variant.
So if a Delta derivative is the next big thing, most likely it will be cooked in the HIV+ population in South Africa and will carry a lot of new mutations that nobody anticipated.
Then we will spend a year studying the effects of those mutations (people are still putting out preprints, describing how Alpha/B.1.1.7 gained its fitness advantage on the molecular level, and finding new unexpected aspects of it), until the next variant appears, and so on…
Let’s contrast that summary with media coverage. I don’t mean to pick on the Deseret News, since the press is only as good as its sources, but a November 18 article exemplifies what sure looks like official complacency. The headline, The worst COVID-19 variant yet may arrive this spring, expert says, implies that no big bad new variant is yet on the horizon but who can be sure. It does mention A.30 as reported in Germany as capable of evading the vaccines in October but GM dismissed it then: “I wouldn’t worry about A.30, it was only ever seen twice, last in May.”
In fairness, another variant has reached prime time press, a Delta variant names AY.4.2. As GM explained on October 6:
People are right now worried about AY.4.2, which is AY.4 + Y145H. The suspicion is that with the Y145H mutation it has gained a sialic acid binding site, and thus potentially a new mode of cell entry.
If true, this will be another example of viral evolution completely blindsiding us…
From GM on October 10:
And finally, what should be officially AY.4.2 — AY.4 + S:A22V + S:Y145H — seems to be growing very fast in the UK, but that is anecdotal, databases have not caught up with the annotations yet.
Data is catching up with anecdata. AY.4.2 looks to be even more contagious than Delta, but it might be less dangerous. From Bloomberg on November 18, More Infectious Covid Delta Sub-Variant Spreading Fast in U.K., Survey Shows:
A more infectious new version of Covid-19’s delta variant is spreading fast in the U.K., accounting for about 12% of the samples gathered in the most recent government survey.
That represents a 2.8% daily growth rate for sub-variant AY.4.2 over the course of the REACT survey, from Oct. 19 to Nov. 5, the researchers said. Still, the new sub-variant seemed less likely to cause symptomatic Covid.
Outside researchers cautioned that it’s too early to say for sure whether the new sub-variant is really less likely to make people sick, or whether there are other factors at work. If AY.4.2 was spreading among people who were younger or in places with broad vaccine coverage, “these factors could account for the observed difference,” Simon Clarke, an associate professor in cellular microbiology at the University of Reading, said in a briefing distributed by the Science Media Centre.
Now let’s turn to GM’s and his colleagues’ current cause for pause, B.1.640. GM first mentioned it nearly a month ago and isn’t liking it any better. As he explained in his first message about it, before it had a designation:
This is a very interesting new variant:
This looks like another one of those African variants that are only seen in small numbers when they leave their country of origin because of the lack of sequencing there:
Conserved Spike mutations – P9L, E96Q, Δ136-144*, R190S*, I210T*, R346S, N394S, Y449N, F490R*, N501Y*, D614G, P681H, T859N, D936H* (*seen conserved in all sequenced except French sequence)
Conserved non-Spike mutations – NSP2 – P129L, E272G*; NSP3 – L1301F*, A1537A*; NSP4 – S386F* R401H*, T492I; NSP6 – V149A*; NSP12 – P323l; ORF3a – T32I*, Q57H*; M – I82T; ORF8 – Q27*STOP; N- D22Y, T205I, E378Q (*found in all but one sequence)
So this has a big deletion around 144, a bunch of other NTD mutations (probably that whole epitope is taken out altogether), has R346S, a Y449 mutation (seen in C.1.2), F490 mutation (F490S is the main immune escape mutation in Lambda/C.37), plus N394S, which hasn’t been seen before, and then P681H (FCS mutations) and T859N (see in other aggressive variants).
Looks quite bad both in terms of contagiousness (because of P681H) and immune escape — NTD epitopes are gone, and it has big bad mutations in all the epitopes in the RBD.
It probably won’t take over though because it does not have P681R, unless selection regime changes.
But it shows that there are still non-Delta survivors out there that might stumble upon a game-changing mutational innovation.
Jerusalem Post wrote about it on November 13 in New COVID variant found in France: Reason for panic or not quite yet? after it spread to Europe. Key sections:
A new COVID variant identified in a handful of European countries is raising concerns among some health professionals because there are changes to the coronavirus spike protein that have never been seen before.
The variant, known either as B.1.X or B.1.640, was first reported by the French paper Le Telegramme after it infected 24 people at a French school in the Brittany region last month. When the variant was discovered in France, the school at which the outbreak occurred was forced to close half of its classes, Le Telegramme reported.
A handful of cases were also discovered in the United Kingdom, Switzerland, Scotland and Italy, although the Delta variant and its descendants continue to be the most dominant strains.
As GM pointed out:
This has nothing to do with Delta, in fact people have really hard time placing in on the tree — it is so far removed from anything else that it just sits on a very long branch of its own.
It also shows a lot of genetic diversity within the ~25 sequences that are available so far, which is a mystery on its own. Usually that suggests a lot of circulation out of sight somewhere where they don’t sequence a lot. Congo-Brazzaville does fit the description, but it is still interesting that it only came out now. My guess is it was festering somewhere in the countryside there, then it made its way to Brazzaville, which is probably the only place in Congo where they sequence anything, and from there it got to France. And from France it got to California, the UK, Italy, Switzerland, and now the Netherlands too (there was another sequence posted yesterday).
Africa is just a black hole in terms of surveillance.
They do an excellent job in South Africa relative to the other countries, to the extent that we even know that for some mysterious reason, the region about Port Elizabeth is specifically the one that produces the most nasty variants — both B.1.351 and B.1.638 all seem to trace to there, not entirely sure about C.1.2 — but even then it is nowhere near the level of the UK, for understandable reasons. Which is why C.1.2 and B.1.638 show up all of a sudden and you already see a complex mix of subvariants indicating long cryptic spread and diversification that nobody noticed.
But the rest of the continent is just largely a blank.
The Tanzanian A.30 variant was only spotted in South Africa in travelers.
B.1.620 seems to have originated in the Cameroon/CAR/Congo-Brazzaville neighborhood (most likely southeastern Cameroon), but was only identified in Lithuania of all places.
And so on.
There is barely any monitoring.
Starting with cases and deaths — based on a few case studies, it appears that most urban areas in Sub-Saharan Africa are at 50-80% serpositivity and have lost 0.2% or more of their population (with median age 20 or so) but official numbers undercount, often by factors of 100x or more.
Sequencing? Forget it.
Perhaps more important than whether B.1.640 turns out to both significantly evade the vaccines and be reasonably contagious is that the officials and the press are making forecasts that are far out on the optimism end of the spectrum. GM pointed out that a very realistic future is one with lots of variants, so that getting vaccinated or having been infected only protects patients from some of them.
And GM pointed out it’s not as if you new variants as the reason to be careful:
Another blatant example of denial:
As the YouTube algorithm these days is giving you only links to corporate mainstream media, I got this suggested to me:
Q: Could this year’s winter surge be as bad as last year’s
Answer from “expert”: No, we’ve experienced our Delta wave.
Of course this year’s summer surge was 2.5x the size of last year’s. So the default guess should have been that the winter surge would be 2.5x worse too.
And you don’t need a new variant to have another wave, it’s as if everyone has forgotten that in 2020 there were three waves and the big winter one was driven by plain vanilla B.1 varieties (B.1.2 was the main one, which had no spike mutations other than D614G). Which is ironically why the “experts” were telling everyone that the virus has “exhausted its evolutionary potential” and no major antigenic drift is to be expected. Which, had it been the case, would pose the very obvious question regarding how the hell these viruses diversified so much in bats and circulated in them for millions of years, but there is no place for logic and reason when peddling hopium to placate the masses…
So keep your guard up! Winter, or as Lambert put it, people in close quarters indoors in poorly ventilated spaces, is coming!