Thread by @michaelzlin

Just out: a new study of immunity against Omicron after vaccines or infection + vaccines.

Simple takeaway: you need 3 hits, whether vaccine or infection, for high antibodies

Interesting nuance: infection has a head start over vax but dose #3 closes it

nature.com/articles/s4159…

This study aims to address what is necessary for high levels of Omicron immunity. As we should define adjectives quantitatively if possible (thinking of a particular big pharma), we can define "high levels" as those associated with >75% disease protection in clinical observations

So let's take a look at the findings. They're very comprehensive, so there are a lot of comparisons to parse. Unfortunately graphs are arranged by # of vax doses, not # of immunity events (ugh). I hope you like brainteasers.

Let's start with Fig 1a vs Fig 1b.

So to compare infection with the first vax dose, we should compare the orange bars in Fig 1a with the blue bars in Fig 1b. The vaccine here is Pfizer. EU1 = early isolate.

Immunity post-infection is stronger (higher) and broader (extends to Omicron) than 1 vax dose. Good to know

Likewise we can compare infection+PF to PF+PF (where each PF is one dose of Pfizer vaccine). Infection+PF is still stronger and broader than PF+PF.

Should mention these are neutralization assays on real virus to measure neutralizing antibodies (nAbs).

Another finding that appears baffling at first is that infection+PF+PF is no different than infection+PF. Does it mean infection+PF is "maxed out" for strength and breadth? No, as we will see later.

Rather it's likely vax dose 2 is too soon after vax dose 1 to make a difference

In fact if the doses were spaced further apart (here they were 3 weeks on average, but we now know optimal is 12 weeks), then it's possible PF+PF would have been as good as infection+PF. That's just speculation though; we don't have data yet.

In fact some infected didn't get PF dose 2. nAbs 7mo later were still: infection+PF = infection+PF+PF > PF+PF.

But the terminology for these groups is confusing:
infection+PF+PF = conv
infection+PF = conv w/o vax #2
PF+PF = naive

Note waning is ~3x for all vs prev measurement

Finally, we see what happens after a late dose 3. Now it's:
PF+PF+latePF
= infection+PF+latePF
= infection+PF+PF+latePF.

So a late dose 3 is the great equalizer: now the never-infected do nearly as well as the infected.

It also suggests immunity is close to "maxing out"

A few things of note:

To circle back, the higher and broader responses of infection+PF+latePF (panel g) vs infection+PF+earlyPF (panel c) means immunity was not "maxed out" at infection+PF (panel b). So that suggests infection+PF+earlyPF wastes dose2 by giving it too early.

Second the fact that PF+PF+latePF is similar to infection+PF+latePF shows 3 hits are fine in the end, even if the first PF shot is not as good as the infection (see panel a vs panel b, in the first figure shown above)

Lastly, however, Omicron nAb levels in PF+PF+latePF are more variable than after infection+PF+latePF. Could be that PF vax presents a restricted set of epitopes and some people don't create the antibodies (which is a random process) to hit the epitopes conserved across variants.

Good thing: Omicron nAbs in most PF+PF+latePF are higher than nAbs to the early strain post-infection (g vs a), which was associated with ~60% protection.

And now the big question is whether nAbs might persist for longer after the 3rd stimulation. We'll know in 5mo.

BTW, a 3-hit rule is both simple and completely expected. It's what we use already for most vaccines, as @zeynep points out.

https://twitter.com/zeynep/status/1486705135602577408

Finally, as a J&J dose is at best like one infection, this supports 3 earlier studies (from Lyke, Balasz, and de Vries) showing that J&J + RNA is not enough to produce sufficient Omicron immunity. And J&J + J&J is much worse and should be un-recommended.

https://twitter.com/michaelzlin/status/1488724488262873090

So this is a clear case of the evidence leading to a recommendation of 3 hits for everyone regardless of vaccine type, except you can only use J&J once. I recommended a 3-shot rule in December:

https://twitter.com/michaelzlin/status/1471262595478790148

Conveniently, 3 exposures as the rule would also be easier to remember, rather than CDC's Twister-like recommendations. Thus "3 strikes and COVID's out" would be both following the science and communicating well. CDC says they try to do both. Will they?

Aha, durability of responses after dose 3 was recently reported by Moderna. After dose 2, nAbs decreased 8x over 7mo for ancestral. After dose 3, this became 2x for ancestral, but 6x for Omicron.

Fits most anti-Omicron B cells arising at/after shot 2

nejm.org/doi/full/10.10…