Thread by @macroliter

All 3 FDA authorized COVID-19 vaccines in use here in USA employ a prefusion “locked” Spike, a beautiful innovation developed by @McLellan_Lab @BarneyGrahamMD @KizzyPhD & others..

https://twitter.com/macroliter/status/1375791645661270016

which results in superior antibody responses because it trains the immune response on the right target 🎯

This is important because the Spike (like all viral membrane fusion proteins has 2 forms: a prefusion form, and a postfusion form..

The prefusion form is the one you want antibodies against. The postfusion form is what the Spike looks like after it has already done its deed..

Which is to deliver the virus’ RNA genome into your cells..

AstraZeneca Oxford & Gamaleya Sputnik V vaccines do not use this strategy of locking the spike in the prefusion conformation.

For this reason, those native spike shots are less likely to work well against variants—

lower titers of antibodies and fewer B-cell clones developed against the correct target means less margin for error when the virus mutates and comes up with new Spike variants..

Here is @McLellan_Lab’s CLASSIC 2017 paper that laid the groundwork for locking the SARS-CoV-2 Spike. He first pulled it off with the Spike of MERS, a related & also very dangerous coronavirus pnas.org/content/114/35…

I should also acknowledge @goodwish916 who played a very big role in a lot this work, too!

And also worth noting that before they got around to coronaviruses like MERS and SARS2, @McLellan_Lab @BarneyGrahamMD locked the respiratory syncytial virus fusion protein, “F”.. which is from an entirely different virus family (paramyxoviruses) science.sciencemag.org/content/340/61…

My bad here is the actual paper where they locked RSV F. science.sciencemag.org/content/342/61…

..back to SARS-CoV-2, here’s Jason’s lab’s latest locked 🔒 Spike, “HexaPro,”which has 6 proline substitutions instead of just 2. It is likely an even better immunogen. science.sciencemag.org/content/369/65…

Peter Palese & @florian_krammer are already testing HexaPro using a Newcastle Disease virus (NDV) vector in human volunteers!

https://twitter.com/florian_krammer/status/1371486646235987970