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

## TL;DR

This paper introduces a model to predict the effectiveness of monoclonal antibodies against SARS-CoV-2 variants by adjusting for viral changes, using data from clinical trials.

## Contribution

A novel variant-adjusted threshold of protection model for monoclonal antibody efficacy in pre-exposure prophylaxis against SARS-CoV-2.

## Key findings

- The ToP model accurately predicted variant-specific efficacies with high concordance in external validation.
- The model integrates neutralizing antibody titers against multiple SARS-CoV-2 variants into a single framework.
- It can serve as a surrogate endpoint in immunobridging studies for faster regulatory approval of mAbs.

## 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.

Neutralising antibody levels are an important correlate of protection for pre-exposure prophylaxis against COVID-19, but it can be difficult to account for immune evasion of emerging virus variants. Here the authors present a variant-adjusted threshold of protection model, developed and validated with data from two clinical trials, which can be used to infer efficacy against any SARS-CoV-2 variant.