Lab studying molecular evolution of proteins and viruses. Affiliated with @fredhutch @HHMINEWS @uwgenome.

Seattle, WA
Joined June 2014
Much of the antibody escape in #Omicron is simply due to fact it has mutations in the RBD epitopes where many neutralizing antibodies bind: nitter.net/jbloom_lab/statu… (2/n)
Replying to @jbloom_lab
What about Omicron? Here’s how all 15 mutations in Omicron RBD affect antibody binding. Seems dire: all biggest peaks are gone. If you explore interactively at jbloomlab.github.io/SARS2_RB… you’ll see mutations at sites 417, 446, & 484 biggest culprits, but others contribute too. (7/n)
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But this isn't the whole story: David Ho's group showed S371L substantially reduces neutralization by a number of antibodies that definitely do *not* bind to an epitope that contains site 371: nitter.net/jbloom_lab/statu… (3/n)
Replying to @jbloom_lab
Further updating on #Omicron antigenic mutations, noting this excellent pre-print by David Ho (biorxiv.org/content/10.1101/…) shows S371L strongly reduces neutralization by a number of antibodies that definitely do *not* have this site in their direct footprint.
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Now a new paper by @priyam2021 @sophie_gobeil @RoryCHenderson @RoryCHenderson @VictoriaStalls shows that the S371L, S373P, and S375F mutations are associated with a more tightly packed down conformation of the RBD: nitter.net/priyam2021/statu… (4/n)
Replying to @priyam2021
We observed a tightly 3-RBD-down domain organization orchestrated by an interfacial loop with three mutations S371L, S373P, S375F.
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They suggest this may be mechanism to partially escape antibodies that bind only RBD-up conformations. In agreement, David Ho data in Tweet 3 of this thread shows S371L mostly affects class 1 antibodies (which bind RBD down) rather than class 2 antibodies (bind RBD up) (5/n)
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Sorry, typo in last Tweet. Should say "partially escape antibodies that bind only RBD-**down** conformations."
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For study, @LaurenEGentles performed neutralization assays on sera collected at ~2-3 & ~6-7 months post-infection in children & adults. In general, neutralization titers declined moderately over this time frame in both groups, in line w similar results reported by others. (2/n)
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In our study, neutralization titers were a bit lower in children than adults at early time point, but there was no longer a difference at later times. (3/n)
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The interesting difference came when we look at anti-N (nucleocapsid) antibody titers. Children had much lower levels of anti-N antibodies than adults at both early and late timepoints post infection (see below). (5/n)
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What does this mean? Anti-N antibodies are not neutralizing (those are the anti-spike antibodies) & probably do not play a major role in protection. In fact, N isn't even in most vaccines. So this difference may mean nothing for protection. But it is interesting because...(6/n)
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N is much more conserved across CoVs than spike. There is little cross-boosting of neutralizing antibodies between #SARSCoV2 & "common cold" beta-Covs OC43/HKU1, because neutralizing spike epitopes are so different. But conservation of N could mean much more cross boosting. (7/n)
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Also, adults obviously have more lifetime common-cold CoV infections than children. So we *speculate* (this is currently just speculation) that adults have higher levels of pre-existing anti-N B-cells that are further then boosted by #SARSCoV2 infection. (8/n)
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This hypothesis is consistent with work on other viruses. Eg, in elderly adults, influenza vaccination increasingly boosts antibodies to non-neutralizing conserved antigens like flu nucleoprotein & even egg-derived contaminants in the vaccine (pubmed.ncbi.nlm.nih.gov/3419…). (9/n)
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This exact phenomenon will not happen w #SARSCoV2 vaccines as they don't contain N or egg (only infection induces N antibodies). But there will be antigenic imprinting from repeated infections/vaccinations. Impact could be good, bad or neutral; see: nitter.net/deeptabhattacha/… (10/n)
Okay, day 2 of kid quarantine (Btw, he is fine and tested negative so far)! Let's dig into original antigenic sin and why IMO the term (not the concept) is too negative. It could start to be a problem at the margins if we boost too often, but I doubt it would prevent updated
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Finally, credit to @LaurenEGentles for leading study & getting pre-print posted. We are grateful to @CDCgov for enabling study. But as has been noted (nitter.net/JoannaMasel/stat…), their manuscript signoff process is extensive & Lauren handled it with grace over last 4 months (11/n)
Replying to @JoannaMasel
Our @CDCMMWR preproposal was rejected. Informal feedback was that they liked it but were so backlogged that a peer reviewed journal was likely faster. This initiated 6 months of clearance procedures needed for CDC coauthor to stay on paper 4/14
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Bloom Lab retweeted
1/18 "Selection analysis identifies unusual clustered mutational changes in Omicron lineage BA.1 that likely impact Spike function" biorxiv.org/content/10.1101/… with @DarrenM98230782 @jbloom_lab @Tuliodna @SpyrosLytras @robertson_lab and many others.
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