Tweet
Nat Commun
. 2025 Oct 14;16(1):9101.
doi: 10.1038/s41467-025-63972-4. A SARS-CoV-2 variant‑adjusted threshold of protection model for monoclonal antibody pre-exposure prophylaxis against COVID-19
Rhiannon Edge # 1 , Sam Matthews # 1 , Bahar Ahani 2 , Anastasia A Aksyuk 3 , Lindsay Clegg 4 , John L Perez 5 , Mark T Esser 5 , Lee-Jah Chang 5 , Ian Hirsch 1 , Tonya Villafana 5 , John Pura 6 , Oleg Stepanov 7 , Katie Streicher 3 , Tom White 1 , Taylor S Cohen 5 , Dean Follmann 8 , Peter B Gilbert 9 , Seth Seegobin 10
Affiliations
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.
. 2025 Oct 14;16(1):9101.
doi: 10.1038/s41467-025-63972-4. A SARS-CoV-2 variant‑adjusted threshold of protection model for monoclonal antibody pre-exposure prophylaxis against COVID-19
Rhiannon Edge # 1 , Sam Matthews # 1 , Bahar Ahani 2 , Anastasia A Aksyuk 3 , Lindsay Clegg 4 , John L Perez 5 , Mark T Esser 5 , Lee-Jah Chang 5 , Ian Hirsch 1 , Tonya Villafana 5 , John Pura 6 , Oleg Stepanov 7 , Katie Streicher 3 , Tom White 1 , Taylor S Cohen 5 , Dean Follmann 8 , Peter B Gilbert 9 , Seth Seegobin 10
Affiliations
- PMID: 41087376
- PMCID: PMC12521407
- DOI: 10.1038/s41467-025-63972-4
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.