A SARS-CoV-2 variant‑adjusted threshold of protection model for monoclonal antibody pre-exposure prophylaxis against COVID-19

Rhiannon Edge, Sam Matthews, Bahar Ahani, Anastasia A. Aksyuk, Lindsay Clegg, John L. Perez, Mark T. Esser, Lee-Jah Chang, Ian Hirsch, Tonya Villafana, John Pura, Oleg Stepanov, Katie Streicher, Tom White, Taylor S. Cohen, Dean Follmann, Peter B. Gilbert and Seth Seegobin ()
Additional contact information
Rhiannon Edge: AstraZeneca
Sam Matthews: AstraZeneca
Bahar Ahani: AstraZeneca
Anastasia A. Aksyuk: AstraZeneca
Lindsay Clegg: AstraZeneca
John L. Perez: AstraZeneca
Mark T. Esser: AstraZeneca
Lee-Jah Chang: AstraZeneca
Ian Hirsch: AstraZeneca
Tonya Villafana: AstraZeneca
John Pura: AstraZeneca
Oleg Stepanov: AstraZeneca
Katie Streicher: AstraZeneca
Tom White: AstraZeneca
Taylor S. Cohen: AstraZeneca
Dean Follmann: National Institutes of Health
Peter B. Gilbert: Fred Hutchinson Cancer Center
Seth Seegobin: AstraZeneca

Nature Communications, 2025, vol. 16, issue 1, 1-14

Abstract: Abstract Clinical development of monoclonal antibodies (mAbs) against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is challenging due to rapid changes in the variant landscape. This study identified a threshold model for neutralising antibody (nAb) titres associated with clinically relevant protection against symptomatic COVID-19 for vulnerable populations. Using efficacy data from the phase 3 PROVENT pre-exposure prophylaxis trial of tixagevimab–cilgavimab (NCT04625725), individual nAb ID50 titres were predicted by dividing serum mAb concentration by prevalence-adjusted tixagevimab–cilgavimab potency (from in vitro IC50 values combined with viral surveillance data) and related to efficacy with a Cox model. The Threshold of Protection (ToP) Cox model was externally validated using data from the phase 3 SUPERNOVA trial (NCT05648110), which assessed sipavibart efficacy against symptomatic COVID-19 in immunocompromised participants. The PROVENT ToP model estimated the variant-specific observed efficacies from SUPERNOVA for 3 and 6 months post any dose with Lin’s concordance of 0.86 and 0.75, respectively. This approach integrates predicted nAb ID50 titres against multiple SARS-CoV-2 variants into a ToP model that can be applied across different variants and could serve as a surrogate endpoint in immunobridging studies to expedite clinical evaluation and regulatory approval for mAbs targeting SARS-CoV-2.

Date: 2025
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DOI: 10.1038/s41467-025-63972-4

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