Work

ACE2 inhibition ELISA is an effective surrogate for SARS-CoV-2 live virus neutralisation

Year: 2025

Type: article

Abstract: BackgroundNeutralising antibodies are a candidate correlate of protection against SARS-CoV-2 and have underpinned regulatory immunobridging strategies. Gold-standard live-virus microneutralisation (MNA) assays are technically demanding, limiting scalability in high-throughput or resource-limited settings. More practical immunoassays that reflect neutralisation capacity are needed to support rapid cross-neutralisation and vaccine efficacy assessments, particularly against variants of concern (VoC). We evaluated the Meso Scale Discovery (MSD) ACE2 inhibition assay (ACE2i) as a surrogate for neutralisation, comparing it with MNA and total anti-spike IgG assays across ancestral and VoC spike proteins.MethodsWe analysed 103 serum samples from immunocompromised participants in the UK OCTAVE-DUO phase 3 trial of COVID-19 vaccination. Responses to ancestral, Delta (B.1.617.2), and Omicron (BA.1) spike proteins were measured by MNA, ACE2i, and MSD total IgG ELISA. Fold-changes from baseline to day 21 post-vaccination and correlations between assays were assessed using Kruskal-Wallis and Spearman correlation.ResultsAll assays detected significant antibody increases after booster vaccination (p < 0.0001): MNA 81.7-fold, IgG 64.8-fold, and ACE2i 27.2-fold. Neutralising titres declined substantially against VoC, with ~20-fold reductions for Omicron in MNA and ACE2i. IgG titres showed only a 6-fold reduction to Omicron and no significant decrease to Delta, suggesting overestimation of functional neutralisation in the presence of RBD escape mutations. Correlations with MNA were strong for the ancestral strain (r > 0.9 for both assays), but declined against VoC. For Delta: ACE2i r = 0.70, IgG r = 0.77; for Omicron: ACE2i r = 0.66, IgG r = 0.57. ACE2i maintained stronger correlations across VoC than IgG.ConclusionThe MSD ACE2i assay is a scalable, functional surrogate for live-virus neutralisation, outperforming IgG binding assays in tracking vaccine efficacy across variants. It is well suited for immunobridging, vaccine evaluation, and variant monitoring where MNA is impractical.

Source: Vaccine

DOI: 10.1016/j.vaccine.2025.128123

Authors: T. Tipton, S. Laidlaw, D. Nguyen, S. Longet, E. Barnes, M. Carroll

Institutions: Centre for Human Genetics, University of Oxford, NIHR Oxford Biomedical Research Centre, Oxford University Hospitals NHS Trust

Language: English

Topic: SARS-CoV-2 and COVID-19 Research

Subfield: Infectious Diseases

Field: Medicine

Domain: Health Sciences

SDG: Good health and well-being

Open Access status: hybrid

Estimated APC paid: $3,620