Thread by @GuptaR_lab

Sharing our Delta work with @AnuragAgrawalMD @flaxter @DrSamirBhatt @wendybarclay11 @CambridgeBRC @Gui_Pap , INSACCOG, Leo James lab LMB, proposing Delta’s explosive emergence in India lies in increased transmissibility combined with immune evasion. researchsquare.com/article/rs-637…

Is Delta 25% more transmissible😑? 50%😳? 100%😱? Read on for the answer...But first: we argue that transmission is only half the story! Breakthrough infections and our lab studies point towards significant immune evasion, something seen with Beta and Gamma (but not Alpha).

In India’s second wave, mathematical modelling suggests that Delta reinfected many who had been infected in the first wave. How do we know? @creswapi, @MellanTom, @charliewhittak fit a 2-category Bayesian disease transmission model to genomic surveillance, serology, and deaths.

The model allows us to simultaneously infer both increased transmission and immune evasion for Delta. We find that Delta is both more transmissible and better able to evade prior immunity elicited by previous infection compared to previously circulating lineages.

While there is substantial uncertainty in our estimates, we find that 𝘪𝘯 𝘔𝘶𝘮𝘣𝘢𝘪 the Delta variant was 10% to 40% more transmissible than previously circulating lineages, and able to evade 20 to 55% of the immune protection provided by prior infection with non-Delta virus.

We then looked at biological evidence for increased transmissibility and immune evasion. 1.Transmissibility: this can result from different aspects of the virus life cycle. eg more particles v more infectious particles

We used a virus isolate and infected airway 3D organoids to mimic the upper respiratory tract. The Delta variant was more efficient at infecting these cells over two days of infection compared to Alpha and the virus appeared to have more processed spike on its surface.

We then tested the ability of spike proteins from Delta to enable virus entry into airway cells using a pseudotyped virus system and saw a significant enhancement that again appeared to be associated with an increased amount of cleaved/processed spike on the surface.

Having shown the Delta virus indeed has greater replication and spike mediated entry efficiency (explaining greater transmissibility), we turned to immune evasion and looked at how well antibodies in blood from people infected during the first UK wave inhibited the Delta variant

We then turned to sera containing neutralising antibodies from vaccinees to test whether this was able to block the Delta variant from causing infection in cells. We found the serum was 8-9 times less effective at blocking the Delta variant compared to wild type virus.

To examine whether this in vitro immune evasion could be observed in humans, we looked at over 100 infections occurring in vaccinated health care workers across 3 hospitals during the wave of COVID-19 in India during March and April 2021.

We found that infections were not severe in the vast majority of vaccinated HCW. However what worried us was the larger average size of transmission clusters in HCW for the Delta Variant versus other Variants (cluster size 3.3 v 1.1, p<0.05) even after adjustment.

Summary:The Delta variant has significant immune evasion and fitness compared to Alpha. Vaccines will prevent severe disease/death in *most* people, but special measures may be needed for those who respond poorly to vaccination. Infection in vaccinated HCWs needs to be considered