Neutralising antibodies are a candidate correlate of protection against SARS-CoV-2, typically they are measured using live virus neutralisation assays, however, these involve high containment work, are technically demanding and can have a long turn-around time. Therefore, surrogate assays are needed to support rapid screening and vaccine trials. Here, we assessed the Meso Scale Discovery (MSD) ACE2 inhibition assay (ACE2i) as a surrogate by comparing it with live virus neutralisation and total anti-spike IgG across ancestral, Delta, and Omicron SARS-CoV-2 spike proteins. Serum from 103 immunocompromised participants in the UK OCTAVE-DUO trial were analysed at baseline and 21 days post-booster. All assays detected significant post-vaccination increases, but micro-neutralisation assay (MNA) and ACE2i showed marked reductions against VoC, particularly Omicron and this was in contrast to IgG assays. The ACE2i assay offers a rapid, scalable, low containment surrogate for neutralisation to support the licensure of new SARS-CoV-2 vaccines and variant monitoring.