tetano
Editor, Senior Moderator
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[SUP] #[/SUP][SUP] 1 [/SUP], Sam Matthews[SUP] #[/SUP][SUP] 1 [/SUP], Bahar Ahani[SUP] 2 [/SUP], Anastasia A Aksyuk[SUP] 3 [/SUP], Lindsay Clegg[SUP] 4 [/SUP], John L Perez[SUP] 5 [/SUP], Mark T Esser[SUP] 5 [/SUP], Lee-Jah Chang[SUP] 5 [/SUP], Ian Hirsch[SUP] 1 [/SUP], Tonya Villafana[SUP] 5 [/SUP], John Pura[SUP] 6 [/SUP], Oleg Stepanov[SUP] 7 [/SUP], Katie Streicher[SUP] 3 [/SUP], Tom White[SUP] 1 [/SUP], Taylor S Cohen[SUP] 5 [/SUP], Dean Follmann[SUP] 8 [/SUP], Peter B Gilbert[SUP] 9 [/SUP], Seth Seegobin[SUP] 10 [/SUP]
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 ID[SUB]50[/SUB] titres were predicted by dividing serum mAb concentration by prevalence-adjusted tixagevimab-cilgavimab potency (from in vitro IC[SUB]50[/SUB] 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[SUB]50[/SUB] 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[SUP] #[/SUP][SUP] 1 [/SUP], Sam Matthews[SUP] #[/SUP][SUP] 1 [/SUP], Bahar Ahani[SUP] 2 [/SUP], Anastasia A Aksyuk[SUP] 3 [/SUP], Lindsay Clegg[SUP] 4 [/SUP], John L Perez[SUP] 5 [/SUP], Mark T Esser[SUP] 5 [/SUP], Lee-Jah Chang[SUP] 5 [/SUP], Ian Hirsch[SUP] 1 [/SUP], Tonya Villafana[SUP] 5 [/SUP], John Pura[SUP] 6 [/SUP], Oleg Stepanov[SUP] 7 [/SUP], Katie Streicher[SUP] 3 [/SUP], Tom White[SUP] 1 [/SUP], Taylor S Cohen[SUP] 5 [/SUP], Dean Follmann[SUP] 8 [/SUP], Peter B Gilbert[SUP] 9 [/SUP], Seth Seegobin[SUP] 10 [/SUP]
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 ID[SUB]50[/SUB] titres were predicted by dividing serum mAb concentration by prevalence-adjusted tixagevimab-cilgavimab potency (from in vitro IC[SUB]50[/SUB] 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[SUB]50[/SUB] 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.