Thread by @roby_bhatt

Reviewed a few preprints on BA.2 immune evasion for a talk. My synthesis:
- BA.1 & BA.2 show similar immune escape from vax
- BA.2 is about as far from BA.1, antigenically, as Beta was from WT
- ppl w prior immunity, then BA.1 infxn, neutralize BA.1 & BA.2 ~equally well

Nerdy 🧵

2/6
I like the "antigenic cartography" model for the variants (medrxiv.org/content/10.110…); I see BA.1 & BA.2 as ~ "antigenically equidistant" from ancestral spike, but kinda far from each other too, similar to the cloud of pre-Omi variants.

But, immunity is complex at this point…

3/6
Folks whose first view of spike was BA.1 (ie, no prior vax or infection) may only be somewhat protected from BA.2 infection (similar to how Beta evaded D614G immunity). But, people with vax, pre-Omi infection, or both; *then* Omi infection, seem to have far broader immunity.

4/6
Boosters give higher Ab titers, but also better breadth: the drop in titer from WT to BA.1 or BA.2 is only ~4-8x in boosted ppl, vs 20-40x after primary vax.

My hunch: it's not just the extra look at spike, but also the time b/w looks that matters (affinity maturation).

5/6
Complexities of prior infxn will prob matter (eg WT, Beta, Delta, etc will impact immunity vs Omi differently), but vaccines should broaden immunity even in ppl w prior infxn. Two studies in NEJM this week support this:
1. nejm.org/doi/full/10.10…
2. nejm.org/doi/full/10.10…

6/6
Suggests an Omicron-spike vaccine might help broaden immunity too… looking forward to data on that.

Links to papers/preprints for the above:
nejm.org/doi/pdf/10.105…
biorxiv.org/content/10.110…
wwwnc.cdc.gov/eid/article/28…
biorxiv.org/content/10.110…

Tx to all authors, & tx for reading.

7/6
One non-immunologist ID doc's thought on an important metric for an Omi-spike vax: neutralization of *all* prior variants in uninfected ppl. Does ancestral, then Omi vax induce broad protection vs WT, Beta, Mu, BA.1, BA.2? No guarantee vs future variants, but broader = better

I never can tell which of my nerdy lit reviews will take off, but this one did, & some ppl asked for a lay summary. It's complex, but I'll try: with BA.2 dominant in the US, how might our immunity hold up? The above thread summarizes data. Here's a long extender aimed at lay ppl.

Evading immunity from vaccines or past infection was the key to Omicron’s success. It did this by having a spike protein that looked very different than prior variants, so our antibodies had trouble binding it, but it still did its job (binding the ACE2 receptor to enter cells).

Prior variants had been immune evasive too: Beta and Mu especially, but also Delta to some degree. Delta dominated the pre-Omicron era b/c it was both a little evasive and really transmissible – but mostly the latter. Delta was a beast. But Omicron was worse than you may think.

Omicron displaced Delta bc it was also really transmissible, but in addition, it was much better at infecting ppl with immunity from either vaccines or past infection. So as Delta was running out of ppl to infect, Omicron spread explosively. Everywhere Omi went, things got worse.

When we say “Omicron”, we have typically meant the BA.1 sublineage, which wreaked havoc this winter. But now BA.2 has swept BA.1 aside - what are the implications? Well, first, BA.2 looks really quite different than BA.1: they have ~20 different spike mutations.

BA.1 had ~33 mutations in spike compared with the original virus. And BA.2 has ~29 mutations from the original. (For comparison, Beta and Delta each had only ~8.) But BA.1 has ~12 mutations not in BA.1, and BA.2 has ~8 unique mutations too. BA.1 and BA.2 are ~20 mutations apart!

Fortunately, despite this mutational distance, BA.2 and BA.1 are more antigenically similar than that might suggest - this isn't a whole new Omicron. So our immune responses will be primed to at least partly recognize BA.2. How much? Depends on what we’ve seen before & how often.

If BA.1 was your first time seeing SARS-CoV-2 spike (ie you hadn’t been vaccinated or infected before getting Omicron), that big difference between BA.1 and BA.2 will matter: you’ll have some protection vs BA.2, but not that much, at least per the antibody studies I summarized.

But this deep into the pandemic, immunity is complex. If you were vaccinated, then got BA.1, you have broader immunity, bc you’ve seen & responded to two pretty different spike proteins already. This seems to give you much better, though not perfect, defense against BA.2.

If you were infected pre-Omicron and then again with BA.1, you also probably have broader immunity, though this is less studied. If you were infected and vaccinated, in some order, even pre-Omi, that probably helps too. But details matter, probably in unpredictable ways…

…infected with what variant? when? Vaccinated with which vaccine? when? Boosted? How far apart? That probably all matters for breadth & magnitude of immunity, but the impacts become hard to predict. Also, how old are you? How's your immune system? And there’s some randomness too

What does it all mean? ¯\_(ツ)_/¯ BA.2 is a formidable virus, just like every SARS-CoV-2. If you’re non-immune, it’ll find you, and one look at Hong Kong is enough to see it’s serious. But the more immunity you have, the better it’ll be - see New Zealand.

https://twitter.com/jburnmurdoch/status/1503420660869214213

The more we see spike, the better our immune system recognizes it later. And vaccines are still the safest way to see spike: for you, no question, but also for everyone you encounter, & everyone they encounter: infectious diseases are infectious; vaccines aren’t. #VaxUp #BoostUp