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
- Seth Seegobin
2025-10-14
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 ID 50 titres were predicted by dividing serum mAb concentration by prevalence-adjusted tixagevimab–cilgavimab potency (from in vitro IC 50 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 ID 50 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.