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jbloom_lab's profile
Bloom Lab
Bloom Lab
Bloom Lab
@jbloom_lab

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Bloom Lab

@jbloom_lab

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

Seattle, WA
research.fhcrc.org/bloom/en.html
Joined June 2014

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    Bloom Lab‏ @jbloom_lab 5 Jan 2021

    We mapped how all mutations to #SARSCoV2 receptor-binding domain (RBD) affect recognition by convalescent polyclonal human sera (https://biorxiv.org/content/10.1101/2020.12.31.425021v1 …). Among implications: E484K (South African lineage) worrying for immune escape; RBD mutations in UK lineage less so (1/n).

    5:02 AM - 5 Jan 2021
    • 972 Retweets
    • 1,859 Likes
    • Matt Jones Meaningful Minority ScienceStop Matthew Juzefyk Myrne Stol Bryson Herrick Laura Daari-Herman D. A. Majid Trek Fan
    55 replies 972 retweets 1,859 likes
      1. New conversation
      2. Bloom Lab‏ @jbloom_lab 5 Jan 2021

        We first determined where in #SARSCoV2 mutations most affect viral neutralization. @veeslerlab had reported RBD-binding antibodies responsible for most neut activity of human sera: https://www.sciencedirect.com/science/article/pii/S0092867420312344 …. We validated w sera from @HelenChuMD's HAARVI cohort (below) (2/n)pic.twitter.com/aGywUHFCsQ

        2 replies 34 retweets 130 likes
        Show this thread
      3. Bloom Lab‏ @jbloom_lab 5 Jan 2021

        Since RBD is main antigenic region (although NTD also important, see below), @AllieGreaney applied method she & @tylernstarr developed for monoclonal antibodies (https://www.sciencedirect.com/science/article/pii/S1931312820306247 …) to map how all mutations to RBD affect binding by *polyclonal* human sera (3/n)

        1 reply 32 retweets 98 likes
        Show this thread
      4. Bloom Lab‏ @jbloom_lab 5 Jan 2021

        Below are escape maps for sera of 4 people (preprint has more). Tall letters mean mutations greatly reduce serum binding. 3 main sera epitopes in RBD. Most important centers on E484 (dark blue), another is 443-450 loop (light blue), last is distal from ACE2 (orange) (4/n)pic.twitter.com/MUBVRNAae9

        4 replies 39 retweets 102 likes
        Show this thread
      5. Bloom Lab‏ @jbloom_lab 5 Jan 2021

        But lots of variation in specificity of anti-RBD immunity among people. For instance, image in previous tweet shows subjects C (& to lesser degree I) focus on E484, subject G focuses on 443-450 loop, and subject K has broad binding not much affected by any single mutation. (5/n)

        1 reply 28 retweets 81 likes
        Show this thread
      6. Bloom Lab‏ @jbloom_lab 5 Jan 2021

        Key results validate in neutralization assays. Mutations at E484 greatly reduce neutralization (>10 fold) by sera from some individuals (examples below). Unfortunately, the South African lineage has E484K, as do some other isolates from elsewhere. (6/n)pic.twitter.com/C3b7Xe8hH7

        4 replies 74 retweets 166 likes
        Show this thread
      7. Bloom Lab‏ @jbloom_lab 5 Jan 2021

        But as escape maps show, effects of mutations differ across individuals. For subject G (below), serum neutralization not much affected by E484K, but reduced >10-fold by G446V. And some sera not much affected by any RBD mutation (eg, subject K in 4th tweet in thread). (7/n)pic.twitter.com/pXnLAP3IOU

        2 replies 37 retweets 101 likes
        Show this thread
      8. Bloom Lab‏ @jbloom_lab 5 Jan 2021

        Also, sometimes effects of mutations change over time for same individual as immune response matures. For subject G below, mutations in 443-450 loop cause big reduction in serum antibody binding at day 18 post-symptom onset, but much less effect several months later. (8/n)pic.twitter.com/2kcV6UVyve

        6 replies 32 retweets 92 likes
        Show this thread
      9. Bloom Lab‏ @jbloom_lab 5 Jan 2021

        Here are neutralization assays validating maps in prior tweet: G446V greatly reduced neutralization by subject G's sera at day 18, but not day 94 (note total overall neut titers change too). So heterogeneity both across people and for a single person over time. (9/n)pic.twitter.com/9z7ZDtVdEx

        3 replies 31 retweets 85 likes
        Show this thread
      10. Bloom Lab‏ @jbloom_lab 5 Jan 2021

        But can make some generalizations based on examples above + rest of data in pre-print. On average, mutations at E484 have biggest effect on polyclonal sera. Also large effects at sites structurally adjacent to E484 (pre-print has list), and in 443-450 loop for some sera. (10/n)

        2 replies 36 retweets 82 likes
        Show this thread
      11. Bloom Lab‏ @jbloom_lab 5 Jan 2021

        These results broadly consistent w other studies that selected RBD mutations that greatly reduce neut by polyclonal sera. See papers by @PaulBieniasz @theodora_nyc @vsv512 @e_andreano @McLellan_Lab: https://www.biorxiv.org/content/10.1101/2020.12.28.424451v1 …, https://www.biorxiv.org/content/10.1101/2020.11.06.372037v1 …, https://elifesciences.org/articles/61312  (11/n)

        1 reply 31 retweets 85 likes
        Show this thread
      12. Bloom Lab‏ @jbloom_lab 5 Jan 2021

        Bloom Lab Retweeted The Menachery Lab

        We do not see strong antigenic effects of N501Y RBD mutation in UK viral lineage, consistent with these data from @TheMenacheryLab (https://twitter.com/themenacherylab/status/1341460343168577538 …). Note that N501Y could affect transmissibility, and UK lineage also has NTD mutations (more on that below). (12/n)

        Bloom Lab added,

        The Menachery Lab @TheMenacheryLab
        At least for N501Y, there is not huge shifts in neutralization based on sera from previously infected COVID patients. UK Variant has other spike mutations that could impact neutralizations. This does not say anything about transmissibility or infection.
        Show this thread
        1 reply 35 retweets 94 likes
        Show this thread
      13. Bloom Lab‏ @jbloom_lab 5 Jan 2021

        Here's plot of how mutating RBD sites affects average serum binding (y-axis) vs frequency of mutations (x-axis). E484K in S African lineage most worrying. But others affect some serum to various degrees & no such thing as "average" human when it comes to serum specificity (13/n)pic.twitter.com/0a1dZSAjQ9

        5 replies 33 retweets 84 likes
        Show this thread
      14. Bloom Lab‏ @jbloom_lab 5 Jan 2021

        Importantly, we only looked at RBD muts, since majority of neut activity of most sera from RBD antibodies (2nd tweet of thread). But NTD muts also important; see @10queues @mccarthy_kr @GuptaR_lab @e_andreano @McLellan_Lab: https://www.biorxiv.org/content/10.1101/2020.11.19.389916v1 …, https://www.medrxiv.org/content/10.1101/2020.12.05.20241927v3 … (14/n)

        3 replies 24 retweets 60 likes
        Show this thread
      15. Bloom Lab‏ @jbloom_lab 5 Jan 2021

        Bloom Lab Retweeted Bloom Lab

        This relative role of RBD & NTD mutations consistent w historical evolution of common-cold CoV-229E, where mutations concentrated in receptor-binding loops of RBD, but also in parts of NTD. Here is plot of mutational variability in CoV-229E spike: https://twitter.com/jbloom_lab/status/1339939746068353025 … (15/n)

        Bloom Lab added,

        Bloom Lab @jbloom_lab
        We did additional experiments suggesting much of the antigenic evolution is in the spike's RBD, which is the most evolutionarily variable part of the CoV-229E spike, especially in receptor binding loops (see below & paper for more details). (7/n) pic.twitter.com/TNtLNt2MG3
        Show this thread
        2 replies 29 retweets 70 likes
        Show this thread
      16. Bloom Lab‏ @jbloom_lab 5 Jan 2021

        Bloom Lab Retweeted Bloom Lab

        What do results mean for possible #SARSCoV2 immune escape? Certainly mutations like E484K are concerning. But they *reduce* neut activity, they don't ablate it. Again, look at CoV-229E: takes years of evolution to escape serum neut of most people https://twitter.com/jbloom_lab/status/1339939732529111040 … (16/n)

        Bloom Lab added,

        Bloom Lab @jbloom_lab
        Next we tested how well human sera collected shortly after 1984 neutralized each viral spike. Below is serum from 26 yr old collected in 1985: it neutralizes 1984 virus well, but 10-fold less activity against 1992 virus & no activity against viruses after 2008. (3/n) pic.twitter.com/uj5G4iUNIA
        Show this thread
        2 replies 74 retweets 158 likes
        Show this thread
      17. Bloom Lab‏ @jbloom_lab 5 Jan 2021

        Heterogeneity of mutation effects across sera could be blessing, as mutations that reduce neutralization by some people won't affect others. Look below at how differently evolution of CoV-229E erodes neutralization by different people (Fig 2A of https://www.biorxiv.org/content/10.1101/2020.12.17.423313v1 …) (17/n)pic.twitter.com/h39rvjiDsz

        1 reply 31 retweets 90 likes
        Show this thread
      18. Bloom Lab‏ @jbloom_lab 5 Jan 2021

        Heterogeneity also shown by @e_andreano @RommieAmaro @McLellan_Lab, who found multiple mutations that greatly (300-fold) reduce neut of #SARSCoV2 by one human serum but often only modestly (a few fold) affect other sera: https://www.biorxiv.org/content/10.1101/2020.12.28.424451v1 … (18/n)

        1 reply 23 retweets 69 likes
        Show this thread
      19. Bloom Lab‏ @jbloom_lab 5 Jan 2021

        Scientifically, we see two priorities going forward: (a) Perform similar studies of vaccine sera. Is vaccine immunity affected by mutations similarly to natural immunity? (b) Monitor for antigenic mutations so vaccines can eventually be updated if needed. (19/n)

        2 replies 46 retweets 161 likes
        Show this thread
      20. Bloom Lab‏ @jbloom_lab 5 Jan 2021

        But biggest priority is vaccinate! Despite above, I'm confident current vaccines will be useful for quite a while. Reasons: (a) even worst mutations (ie, E484) only erode neut activity of some sera, don't eliminate it for any, (b) current vaccines elicit strong immunity... (20/n)

        8 replies 144 retweets 376 likes
        Show this thread
      21. Bloom Lab‏ @jbloom_lab 5 Jan 2021

        ... (c) evidence in animals (& from humans after 1st vaccine dose) that modest immunity can blunt disease, (d) natural immunity to seasonal CoV provides some homologous protection for 3+ years even though they evolve too (see https://wellcomeopenresearch.org/articles/5-52 ) (21/n)

        1 reply 50 retweets 140 likes
        Show this thread
      22. Bloom Lab‏ @jbloom_lab 5 Jan 2021

        Finally, most credit goes to @AllieGreaney, the outstanding grad student who led our study. She worked with Andrea Loes, @khdcrawford, @tylernstarr, & Keara Malone. @HelenChuMD was our invaluable clinical collaborator, and thanks to the volunteers in her HAARVI cohort (22/n)

        8 replies 22 retweets 156 likes
        Show this thread
      23. Bloom Lab‏ @jbloom_lab 5 Jan 2021

        I'd also like to call out the important work by @houzhou @Tuliodna and cowoerkers in characterizing lineage 501Y.V2 initially identified in South Africa, which carries RBD mutations including E484K, which our study suggests has an antigenic effect: https://www.medrxiv.org/content/10.1101/2020.12.21.20248640v1.full-text … (23/n)

        1 reply 21 retweets 68 likes
        Show this thread
      24. Bloom Lab‏ @jbloom_lab 5 Jan 2021

        Our functional work is potentially useful because the high-quality viral surveillance and rapid reporting of data exemplified by their study. I'd also like to correct terminology earlier in this Tweet chain. It is lineage 501Y.V2, initially identified in South Africa. (24/n)

        1 reply 17 retweets 49 likes
        Show this thread
      25. Bloom Lab‏ @jbloom_lab 5 Jan 2021

        It should be referred by full lineage, not country as in my earlier Tweet. In addition, E484K has been independently observed in viruses from other locations, so any antigenic impacts of this mutation is *not* a concern confined to any country or viral lineage. (25/n)

        5 replies 25 retweets 78 likes
        Show this thread
      26. Bloom Lab‏ @jbloom_lab 5 Jan 2021

        Bloom Lab Retweeted Dr Emma Hodcroft

        One more Tweet to share data by @firefoxx66 inspired by useful comments from @Tuliodna. Please read this: https://twitter.com/firefoxx66/status/1346546912644759553?s=20 … Key implication: the E484K mutation was most prominently reported by @Tuliodna in the 501Y.V2 lineage first identified in South Africa. (26/n)

        Bloom Lab added,

        Dr Emma HodcroftVerified account @firefoxx66
        Following some increased interest tonight in S:E484, a new focal build is now up! This build is created by pulling out all sequences with a mutation at nucleotide 23012 & adding background sequences. 1/8 @jbloom_lab @Tuliodna https://nextstrain.org/groups/neherlab/ncov/S.E484K?c=gt-S_484 … pic.twitter.com/pk715GPusc
        Show this thread
        1 reply 19 retweets 39 likes
        Show this thread
      27. Bloom Lab‏ @jbloom_lab 5 Jan 2021

        But importantly, muts at E484 arisen multiple times in several countries over last 9 months. Our functional work (& others cited above) show E484 muts antigenically important. And surveillance by @Tuliodna @rjlessells @atrvlncc & others show this mutation is circulating (27/n)

        1 reply 22 retweets 47 likes
        Show this thread
      28. Bloom Lab‏ @jbloom_lab 5 Jan 2021

        But because this mutation has arisen multiple times in multiple locations, it is not a concern confined to any particular country. Instead, globally important to continue to monitor evolution, characterize mutations, & assess any eventual implications for vaccine updates. (28/n)

        12 replies 25 retweets 80 likes
        Show this thread
      29. End of conversation

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