Thread by @veeslerlab

The peer-reviewed version of our manuscript describing the influence of the #SARSCoV2 spike glycoprotein conformation on vaccine- and infection-elicited antibody responses in humans is out!

Led by @johnbowenbio
@HHMINEWS
@UWBiochemistry

science.org/doi/10.1126/sc…

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The original thread describing the @biorxivpreprint can be found here:

https://twitter.com/veeslerlab/status/1473323932388184067

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During the review process, we expanded our panel of vaccinee plasma samples to also include subjects that received 2 doses of Jansen Ad26.COV2.S. or of Novavax NVX-CoV2373, thereby covering all 4 vaccines authorized or approved in the US (and several others used worldwide)

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We show that vaccines containing prefusion-stabilizing S mutations (S-2P) elicit antibody responses in humans with enhanced recognition of S and the S1 subunit relative to postfusion S, as compared to vaccines lacking these mutations or natural infection.

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We also found that vaccination of individuals previously infected (WA-1, 2020), with one of 3 vaccines tested, also preferentially boosted prefusion S as well as S1 antibody binding titers!

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We extended the correlation between plasma neutralizing activity and the magnitude of antibody responses to the S1 subunit (in addition to S, prefusion S2, RBD, NTD but not postfusion S2) for all vaccines evaluated and for infection-elicited polyclonal antibodies

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We show that depletion of prefusion S or S1 subunit-targeting antibodies resulted in a near-complete loss of neutralizing activity whereas depletion using prefusion or postfusion S2 had no detectable impact.

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It is therefore S1 subunit shedding rather than S2 conformational changes associated with the prefusion to postfusion transition that leads to a marked loss of potency due to the fact that most neutralizing antibodies target the RBD and the NTD.

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This highlights one of the grand challenges we (as a field) have to overcome to elicit broadly neutralizing antibodies against betacoronaviruses or even all coronaviruses!

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Towards this goal and as part of this work, we designed and determined a #CryoEM structure of a prefusion S2 trimer (prefusion tertiary structure with more open quaternary structure than prefusion S) described in the supplemental material!

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We hope that you will have as much fun reading this manuscript as we had writing it. Thank you @YoungjunPark11 Cameron Stewart, Jack Brown, William Sharkey, @coronalexington, Anshu Joshi, @sprouse_kaitlin @Dr_MattMcCallum

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And thank you to all our terrific collaborators including @DavideCorti6 @HelenChuMD @simmerling @profshanecrotty @maynard_lab @sallustolab @CPosavad22 @SetteLab @junsionglow_ @SkiClimbSciNick & many others not on Twitter!

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