There's a lineage of Omicron that's gained the R346K mutation (BA.1.1). This one could spell some trouble for the AZ mAb (tixagevimab/cilgavimab, Evusheld) that's being used for pre-exposure prophylaxis. If you want to learn about tix/cil vs Omicron, read on 1/7
Tix/cil (Evusheld) are 2 mAbs that bind non-overlapping RBD epitopes + have Fc changes to make them long-lasting. In the ph3 PROVENT trial, tix/cil given to high-risk uninfected pts resulted in a 77% reduction in symptomatic COVID-19 infxn. It's FDA-authorized for PrEP 2/7
Based on the NIH OpenData portal of aggregate in vitro data against Omicron, tix/cil has 10-100-fold decreased activity (greater loss of activity for tix than cil), but sotrovimab only has a 2-4-fold loss of activity. So how are both considered likely still active vs Omicron? 3/7
It turns out that tix/cil is at baseline far more potent than sotrovimab as nicely outlined by neut curves in this paper (nature.com/articles/s4158…). Even with the bigger loss of activity of tix/cil vs Omicron, the IC50s end up at a similar point compared to sot (red lines) 4/7
Based on the neut curves above and the PK data (biorxiv.org/content/10.110…), tix/cil should be maintained above the IC90s for at least 6 months vs Omicron, which is reassuring. 5/7
However, position 346 is a site of resistance for cilgavimab and R346K will further decrease its activity based on in vitro data (nature.com/articles/s4158…, COV2-2130 = cil in figure below) 6/7
In summary, Evusheld should retain activity vs Omicron despite 10-100-fold decreased activity. But the BA.1.1 version (+R346K) is expected to further decr cilgavimab activity and we should keep a close eye on this variant and monitor for breakthrough infections on Evusheld 7/7
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