The ongoing COVID-19 pandemic is leading to the discovery of hundreds of novel SARS-CoV-2 variants on a daily basis. While most variants do not impact the course of the pandemic, some variants pose significantly increased risk when the acquired mutations allow better evasion of antibody neutralisation in previously infected or vaccinated subjects, or increased transmissibility. Early detection of such high risk variants (HRVs) is paramount for the proper management of the pandemic. However, experimental assays to determine immune evasion and transmissibility characteristics of new variants are resource-intensive and time-consuming, potentially leading to delayed appropriate responses by decision makers. Here we present a novel in silico approach combining Spike protein structure modelling and large protein transformer language models on Spike protein sequences, to accurately rank SARS-CoV-2 variants for immune escape and fitness potential. We validate our immune escape and fitness metrics with in vitro pVNT and binding assays. These metrics can be combined into an automated Early Warning System (EWS) capable of evaluating new variants in minutes and risk monitoring variant lineages in near real-time. The EWS flagged 12 out of 13 variants, designated by the World Health Organisation (WHO, Alpha-Omicron) as potentially dangerous, on average two months ahead of them being designated as such, demonstrating its ability to help increase preparedness against future variants. Omicron was flagged by the EWS on the day its sequence was made available, with immune evasion and binding metrics subsequently confirmed through our in vitro experiments.
One-Sentence Summary A COVID-19 Early Warning System combining structural modelling with AI to detect and monitor high risk SARS-CoV-2 variants, identifying >90% of WHO designated variants on average two months in advance.