🚨New preprint from Legacy study @TheCrick & @UCLHresearch. ⏩biorxiv.org/content/10.1101/…
👉We asked: "What's a 'normal' COVID vaccine response?" 🤔
Turns out there's 2 kinds of 'normal' in healthy adults 🧐 — and this has implications for protection vs. future variants 🤒.🧵 1/n
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Our Legacy study cohort is unique 🤩 b/c
1⃣ we are *very* sure about infection & vax history – incl weekly PCR & viral seq since 2020, and
2⃣ high-throughput live-virus neutralisation data on variants from @MaryYiWeiWu lets us do “big-data” serology x.com/DavidLVBauer/status/15…. 2/n
We adapted the @TheCrick COVID Surveillance Unit’s neutralisation assay to measure this for ourselves. While these assays are not hard to do, they *are* hard to do *reproducibly* & to a high standard (we try!👇) It’s hard for regulators to eval. lots of different results. 4/n
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We used the Legacy study during the COVID pandemic to assess immunity to emerging variants, e.g. Omicron:
x.com/DavidLVBauer/status/14…
Now that the pandemic phase is ending, we’ve been able to start digging into some of the more interesting “WHY?” questions… 3/n
Why not all doom and gloom? ➡️Broad immune response after 3x vax tackles Omicron in @TheCrick / @UCLHresearch Legacy study of 620 samples from 364 participants. 💡 READ ON... Out @TheLancet, by @MaryYiWeiWu, @dremmacbw, @EdjCarr et al. thelancet.com/journals/lance… 🧵 1/n
May 26, 2023 · 7:13 AM UTC
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In healthy UK adults in late 2021, you’d expect to find 3 types of responses:
🟢a few LOW responders to vax (low IgG / immunodef.)
⚫️some with HYBRID immunity from prior infection
🟣most with a distribution of "NORMAL" immune responses to vax
But that's not what we saw🔎... 4/n
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Instead, w/clustering on >2000 data points, “normal” people cluster into 2 clear groups:
🔴BROAD responders: ~60% can neutralise Omicron BA.1 before their 3rd vax dose
🔵NARROW responders: ~40% made a great response to ancestral Wuhan-Hu-1 spike but not vs. later variants
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So, *why* might “normal” people end up being BROAD or NARROW responders to vaccination? There wasn’t anything obvious:
❌No age/sex difference
❌Discrete difference in Anti-S IgG by ELISA
❌mRNA 💉 favoured BROAD, but not whole story
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Since neutralising antibody production is a function of the orchestrated response of B cells & CD4+ T cells after vaccination...
...we investigated the cellular response from 🔴BROAD & 🔵NARROW responders w/mass cytometry, and...
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💡we found specific T cell & B cell populations that were significantly enriched in 🔴BROAD responders *before* their 3rd vax dose:
➡️ an atypical memory B cell population
➡️ a CCR6+ CD4 T cell population
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Interestingly, these T cell & B cell populations have been implicated in immune responses in other contexts (details in preprint: biorxiv.org/content/10.1101/… )
But we know what happened to the Legacy cohort IRL😉! Were 🔴BROAD responders better protected from infection?
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We looked at Omicron BA.2 infections after a 3rd vaccine dose in our Legacy study cohort… and found 🔴BROAD responders to COVID vaccination were indeed significantly better protected than 🔵NARROW responders!
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Summary: We found
1⃣ A dichotomy of “normal” neutralising Ab responses prior to 3rd dose COVID vaccination, with
2⃣ corresponding memory lymphocyte changes, that
3⃣ forecast infection risk based on whether someone was a 🔴BROAD or 🔵NARROW responder (& not on IgG ELISA)
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🚨Overall, our results suggest serological breadth of response to vaccination is *not* a purely stochastic phenomenon.
NEXT QUESTIONS:
👉Are 🔴BROAD and 🔵NARROW groups persistent over time & "pre-set" for an individual?
... 12/n
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👉What is the function of the T cell & B cell sub-populations?
👉Is this relevant to wider Ab responses more broadly beyond vax? Are there consequences e.g. for autoimmunity?
👉Should vax trials consider matching arms by participant breadth responses?
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⚠️Lots more to unpack in the preprint: biorxiv.org/content/10.1101/…
Lastly, thanks to Legacy Study participants, funders & co-authors incl @dremmacbw @DavidLVBauer @bealelab and @Hermsnz @MaryYiWeiWu @cbailey_58 @gavinpaulkelly @viyaasanm @Jerome_Nicod @Artisplicer
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And those who set up the study @TheCrick & @UCLHresearch in the depths of the COVID-19 pandemic to secure the “Legacy” of their work for future research & continue to support it: @CharlesSwanton @LabGandhi, Bryan Williams, Steve Gamblin, @SamBarrell1, & others. Thank you 🙏
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