Thread by @LongDesertTrain

Do you remember BA.3—the weakling cousin of BA.1 & BA.2 that seemed to take the worst from each & had weaker ACE2 binding than even the ancestral Wuhan Virus?

After 3 years, BA.3 is back.

And it is transmitting.

Who saw this coming?
1/13

While the full extent of the new BA.3’s spread is not known, it’s been detected in 2 different South African regions through regular (not targeted) surveillance by @Dikeled61970012, @Tuliodna, & the invaluable South African virology community.
2/13
github.com/cov-lineages/p…

After nearly 3 years of intrahost evolution in a chronically infected person, the new BA.3 is almost unrecognizable. It has ~41 spike AA substitutions (4 of which are 2-nuc muts) to go with 14 AA deletions (∆136-147+∆243-244). We’ve seen nothing like this since 2023.
3/13

The new BA.3 has added 3-4 new glycans in spike at: N101 (via I101T), N185 (K187T), N354 (K356T—in 1/3 sequences), & N529 (K529N). Plus it lacks T19I, so it retains the N17 glycan that we’ve not seen since BA.1 (& which Delta also lacked due to T19R).
4/13

https://x.com/LongDesertTrain/status/1747051506933584159

Like BA.2.87.1, the new BA.3 has rearranged its spike NTD (S:1-325) by eliminating the C15-C136 disulfide bond with P9L (which shunts C15 into the signal peptide, which gets cleaved off) & ∆136-147, which eliminates S:C136.
5/13

https://x.com/LongDesertTrain/status/1753195712622252340

New BA.3 is also looking quite trim and fit these days! Like several late-XBB variants, it has shorn itself of ORF7ab & ORF8 with a deletion of over 800 nucleotides. It appears to be the same deletion that GW.5.1.1 (an XBB) had.
6/13

https://x.com/LongDesertTrain/status/1718769959688360206

As always, there’s a lot to unpack with this new saltation variant. For now, I’ll just briefly mention one fascinating mutation, and save more extensive analysis for later. The new BA.3 has one of my favorite rare, enigmatic mutations: S:A852K.
7/13

S:A852K is a 2-nucleotide mutation that’s appeared almost exclusively in highly divergent chronic-infection sequences. The last sequence to have A852K was a Cryptic-like BA.1 from New York in mid-2023 w/striking similarities to the new BA.3, including...
8/13

...NTD disulfide erasure through P9L + ∆C136, N164K, a new N185 glycan via K187T, the H505Y reversion, H681R, and of course A852K. Fortunately, the new BA.3 does not have the notorious ORF3a:H182D, which seems to kill a disturbing proportion of the people it infects.
9/13

I don’t know what A852K does. K854 used to bond with D614 before D614G became universal, & A852K has appeared with K854N several times. The BA.3 has many mutations in that region, so maybe it affects up/down spike conformation.
10/13 science.org/doi/10.1126/sc…

Will the new BA.3 spread across the world & grow? There’s no way to know. It may sputter & die like BA.2.87.1. But BA.2.87.1 arrived just when JN.1 was sweeping the world & was trampled underfoot. The ground is now more fertile, & a novel-variant seed more likely to bloom.
11/13

It’s been a year and a half since we’ve seen a truly novel variant spread & just saw the weakest winter Covid wave ever. I suspect JN.1 variants have become weaker over time, forced into acquiring infectivity-reducing spike mutations to evade broadening antibodies.
12/13

If the new BA.3 circulates long enough to pick up some transmission-enhancing mutations (think BA.2.86 getting L455S to become JN.1), it could be the next big thing. Or not. Time will tell.

We should see it in other countries pretty soon if it’s the real deal.

13/end