Thread by @DavidLVBauer

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

Two doses doesn’t provide nearly as much neutralisation vs. Omicron, especially for Oxford/AstraZeneca recipients. Titres wane, and for 2xPfizer, ~half have no quantifiable neutralisation vs Omicron after 3 months (but nearly all still neutralise Alpha and Delta) 2/n

Differential in Omicron neutralisation after only 2 doses is much clearer when stratifying by those who reported having prior COVID symptoms *plus* 2 doses vaccine. 3/n

Those who had “breakthrough” infections following 2 vaccine doses (nearly all Delta) produced a strong neutralisation response to Omicron, akin to a 3rd vaccine dose. 4/n

Participants who had a 3rd dose are older (b/c how the UK prioritised boosting), so age-matching our cohort allows a direct comparison: ⏭️THREE doses vs. Omicron gives equivalent tires to ⏩TWO doses vs. Delta... 5/n

... but does that mean a successful booster campaign has 🔄“reset” the 🇬🇧 UK back to July 2021 state??? Maybe. Vaccine efficacy vs symptomatic illness is broadly in line with titres. (it’s lower, but VE data is confounded by older age, and... 6/n

... also possible that changes in Omicron cell type / physiological site of infection (e.g. upper respiratory tract vs lower) means that the level of neutralising antibodies needed for sterilising immunity is now higher. 7/n

vs. last July, we now also have effective antivirals for those that are at risk of severe disease... and some monoclonal Abs still work (our data below shows Xevudy (sotrovimab from Vir/GSK) still neutralises, but Ronapreve (casirivimab/imdevimab from Regeneron) does not. 8/n

Neutralising antibody titres are still a good CORRELATE of protection... in effect they show us a“high water mark” for the overall response vs. Omicron, esp. since their production lies *downstream* of T-cell and B-cell responses. cell.com/immunity/fullt… 9/n

Lots of open questions re. Omicron: how fast do titres wane in different cohorts? What about mRNA-boosted Oxford/AstraZeneca recipients? How much does Omicron breakthrough infection boost titres? (We are working as fast as we can!) 10/n

Going forward, all this will work best if we can pool *AND* standardise results from different labs... a great illustration by Deborah Cromer, David Khoury and colleagues @KirbyInstitute thelancet.com/journals/lanmi… 11/n

We use a set of synthetic controls calibrated to the WHO International Standard that are stable, broadly neutralising, and can be produced in unlimited quantities. We’ll be releasing them “open-source” in the coming year to anyone who wants them. 12/n

It will also still be critical to monitor responses to vaccination against emerging variants in vulnerable populations -- esp. those that don’t respond well to vaccination e.g. those on kidney dialysis @bealelab & w/blood cancer (leukaemia) @TurajlicLab. 13/n

Overall, as the pandemic progresses, we think studies w/large cohorts like ours are important, since they can sample the range of immunological histories that capture much of the present heterogeneity in a population, MORE so than a handful of clinical trial participants...14/n

...and comparison to recent, RELEVANT variants w/rich REAL-WORLD vaccine efficacy data (e.g. Omicron vs. Alpha and Delta) will be much more informative than e.g. the breathless tweets last month trumpeting "🚨20-40x reduction" in neutralisation vs. ancestral Wuhan-Hu-1 spike 15/n

All this work is possible because of the development of a high-throughput live-virus neutralisation assay by @MaryYiWeiWu, @DrUlferts, Ruth Harvey and Mike Howell; and virus isolates from Gavin Screaton @OxfordMedSci distributed by #G2P-UK led by @wendybarclay11 16/n

& by the amazing team @UCLHresearch & @TheCrick pulling together clinicians, virologists, robotics experts, database designers, structural biologists + more to contribute their expertise... and by Bryan Williams, @CharlesSwanton & @LabGandhi who established Legacy study 17/n

...and speaking of which, all this would not be possible without the 🤩 amazing Legacy study participants 🧑‍🤝‍🧑@TheCrick and @UCLH who continue to book up study visits🩸🧪 week after week: THANK YOU!
(PS. get boosted!). 17/17