Here are the slides I am presenting at this morning's @ceirrnetwork.bsky.social seminar related to characterizing the human neutralizing antibody landscape to human seasonal influenza for purposes such as vaccine strain selection: slides.com/jbloom/flu-s...
See the full paper for additional details and analyses:
www.pnas.org/doi/10.1073/...
Thanks to Brendan Larsen for leading study & our collaborators in @veeslerlab.bsky.social lab.
We also defined how F mutations affect neutralization by a panel of monoclonal antibodies. This allowed us to quantify the resilience of different antibodies to escape, and predict which antibodies also neutralize the related Hendra virus.
A strategy for vaccines is to stabilize F in pre-fusion conformation. We identified sites where mutations to proline (which blocks helix formation) are disfavored. This identifies new candidate mutations for stabilizing F vaccine immunogens.
For this study, we used pseudoviruses that can only undergo a single round of cell entry (& so are not human pathogens) to measure how mutations to F affect its fusion function. We found F is more functionally constrained than the other Nipah surface protein, RBP.
In new study led by Brendan Larsen, we map functional constraint across the Nipah virus F protein to define constrained epitopes for antibody targeting and identify mutations that stabilize the prefusion conformation for vaccine immunogens.
www.pnas.org/doi/10.1073/...
In new study we examine constraints on evolution of endemic "common-cold" coronavirus 229E
We find strong tradeoff between antibody neutralization & receptor binding, due to up-down position of spike RBD
www.biorxiv.org/content/10.6...
See lead author Sheri Harari's summary: x.com/SheriHarari/...
The final version of this article has been published in @natecoevo.nature.com alongside a nice News and Views by @seth-zost.bsky.social: www.nature.com/articles/s41...
The final version of record of this study has been published in @elife.bsky.social alongside a nice insight perspective: elifesciences.org/articles/110...
See here for the additional Hensley lab preprint that explains this observation more: bsky.app/profile/did:...
Our preprint examining the specificity of human antibodies that cross-react with subclade K H3N2 viruses was posted this morning on medRxiv. These studies have implications on what vaccine strains should be selected for next year’s influenza season. 1/
www.medrxiv.org/content/10.6...
For instance, in interactive plot below I've moused over to highlight serum from an individual who mostly has high titers, but has dramatically reduced titers just to strains with mutations at site 135. There is no way to represent that sort of thing w just medians and ranges across sera.
But I agree per-sera plot is better with interactive version: mouse over lines to see individual sera: jbloomlab.github.io/flu-seqneut-...
Here is link to plot that shows medians & interquartile range: jbloomlab.github.io/flu-seqneut-...
However, I prefer to look at interactive plots with per-serum titers. Reason that the person-to-person heterogeneity is important for viral fitness, eg elifesciences.org/reviewed-pre...
Also thanks to @ceirrnetwork.bsky.social, @niaidnews.bsky.social, and @hhmi-science.bsky.social for support.
Thanks to all our collaborators:
@huddlej.bsky.social, S Turner, A Loes, J Liu, S Gang, T Griffiths, @troisie.bsky.social, B Cowling, F Ho, N Leung, J Englund, K Lacombe, S Watanabe, H Hasegawa, M Busch, M Lanteri, M Stone, B Spencer, @neher.io, D Smith, T Bedford, @scottehensley.bsky.social
I’d also like to note that @ckikawa.bsky.social was recently given a Beyond the Journal Award for the way she has been sharing these and similar data on GitHub in real-time as they are generated: www.experiment.foundation/beyond
The large neutralization dataset described above provides resolution that can help achieve this goal and inform better vaccine-strain selection.
All data are publicly available at github.com/jbloomlab/fl...
Please explore the visualizations or download them for further analysis!
Of course, lots of people still have good titers to subclade K---and most people didn’t get influenza this year.
But for seasonal vaccines we’d like to identify variants like subclade K which, although not pandemic scale, still make for a bad flu season.
But types of variants we saw early in COVID-19 pandemic (eg, Omicron w ~10-fold titer drop) are not norm for endemic viruses.
H3N2 subclade K shows “only” a ~1.5-2-fold titer drop is enough for variant to spread rapidly & cause worse-than normal influenza season.
So both H3N2 & H1N1 subclades that recently spread have reduced neutralization.
But median titer drop to subclade K (H3N2) and D.3.1.1 (H1N1) only ~1.5-2 fold across 302 human sera. Relative to SARS-CoV-2 variants in 2021-2022, this seems like small titer drop.
For H1N1 influenza, a new subclade (D.3.1.1) has also recently spread to become dominant, and our data show that this new subclade has reduced neutralization by human sera
See jbloomlab.github.io/flu-seqneut-... for interactive version of below plot
The mutations that further reduce neutralization of subclade K are in antigenic regions D & E, which were less mutated in parent subclade K
See below from recent @scottehensley.bsky.social preprint (doi.org/10.64898/202...) & stay tuned for study from their group that explains this observation
For vaccine update decisions, we care about what is NEXT.
Here our data help by showing that within subclade K strains there are already new subvariants w further reduced neutralization.
These subvariants have additional mutations as shown below & interactively at nextstrain.org/community/jb...
Probably because of these lower titers, subclade K has rapidly become dominant among H3N2, rising from <1% to 95% frequency in ~9 months. See below image from this Nextstrain link (nextstrain.org/seasonal-flu...).
Our finding of ~1.5-2-fold lower median titers to subclade K concurs w recent studies by:
@scottehensley.bsky.social - doi.org/10.64898/202...
Barouch lab - doi.org/10.64898/202...
@prmurcia.bsky.social - doi.org/10.64898/202...
Skowronski lab - pubmed.ncbi.nlm.nih.gov/41645799/
Resulting datasets are very rich. Below are H3N2 data (also under first post in this thread).
There is extreme variability among human sera; the median serum has ~1.5-2-fold lower neutralization of subclade K.
See jbloomlab.github.io/flu-seqneut-... to explore interactive plot
Specifically, we first assembled a set of 57 H3N2 and 34 H1N1 strains that largely cover the current diversity of human seasonal influenza (see image below).
We then measured neutralization of all 91 strains against 302 sera from humans of a range of ages (0 to 103 years) and geographic locations.
We used sequencing-based neutralization assays, which measure neutralization of 100s of viruses at once. One grad student @ckikawa.bsky.social measured ~27,000 neutralization curves in ~2 months, w many collaborators sharing sera & helping w analysis
See preprint: www.biorxiv.org/content/10.6...
We have posted data providing real-time measurement of human neutralizing antibody landscape to seasonal influenza.
Data explain spread of subclades K (H3N2) & D.3.1.1 (H1N1), identify subclade K subvariants w reduced neutralization, & can inform choice of strains for next vaccine.