Antiviral effect of Evusheld in COVID-19 hospitalized patients infected with pre-Omicron or Omicron variants: a modelling analysis of the randomized DisCoVeRy trial

Abstract

Background: The antiviral efficacy of Evusheld (AZD7442) in patients hospitalized for SARS-CoV-2 is unknown.

Methods: We analysed the evolution of both the nasopharyngeal viral load and the serum neutralization activity against the variant of infection in 199 hospitalized patients (109 treated with Evusheld, 90 treated with placebo) infected with the SARS-CoV-2 virus and included in the randomized, double-blind, trial DisCoVeRy (NCT04315948). Using a mechanistic mathematical model, we reconstructed the trajectories of viral kinetics and how they are modulated by the increase in serum neutralization activity during Evusheld treatment.

Results: Our model identified that the neutralization activity was associated with viral kinetics. Reflecting the variant-dependent neutralization activity of Evusheld, the antiviral activity of Evusheld was larger in patients infected with pre-Omicron or Omicron BA.2 variants than in patients infected with Omicron BA.1 variant. More specifically, the model predicted that Evusheld reduced the median time to viral clearance compared with placebo-treated patients by more than 5 days in patients infected by pre-Omicron (median: 5.9; 80% PI: 2.1-13.6) or Omicron BA.2 (median: 5.4; 80% PI: 2.0-12.4), respectively. The effect was more modest in patients infected by the Omicron BA.1 variant, reducing the median time to viral clearance by 2 days (median: 2.2; 80% PI: 0.4-8.9).

Conclusions: Hospitalized patients treated with Evusheld had a shorter median time to SARS-CoV-2 viral clearance. As Evusheld antiviral activity is mediated by the level of neutralization activity, its impact on viral clearance varies largely according to the variant of infection.

Figure 1.

Schema of the mechanistic model of viral dynamics, integrating the dynamics of neutralization activity. This figure appears in colour in the online version of JAC and in black and white in the print version of JAC.

Figure 2.

Neutralization activity of Evusheld against the variant of infection. Light lines and dots are individual observations. Solid lines are the mean of each treatment arm. Observations under LoD are imputed to the LoD estimate. This figure appears in colour in the online version of JAC and in black and white in the print version of JAC.

Figure 3.

Viral load in treated and untreated individuals according to the variant of infection. Light lines and dots are individual observations. Solid lines are the mean of each treatment arm. Observations under LoD are imputed to the LoD estimate. This figure appears in colour in the online version of JAC and in black and white in the print version of JAC.

Figure 4.

Model-based evolution of neutralization activity according to the variant of infection. Red: Median and 10–90 prediction interval of neutralization activity in Evusheld-treated individuals; blue: median and 10–90 prediction interval of neutralization activity in placebo-treated individuals. Parameters and patient characteristics are sampled from the viral dynamic model (see Methods). This figure appears in colour in the online version of JAC and in black and white in the print version of JAC.

Figure 5.

Model-based kinetics of viral load according to the variant of infection. Red: Median and 10–90 prediction interval of viral load in Evusheld-treated individuals; blue: median and 10–90 prediction interval of viral load in placebo-treated individuals. Parameters and patient characteristics are sampled from the viral dynamic model (see Methods). This figure appears in colour in the online version of JAC and in black and white in the print version of JAC.

Figure 6.

Model-based cumulative incidence of time to viral undetectability according to the variant of infection. Red: Evusheld-treated individuals; blue: placebo-treated individual. Parameters and patient characteristics are sampled from the viral dynamic model (see Methods). This figure appears in colour in the online version of JAC and in black and white in the print version of JAC.

Figure 7.

Association between the neutralization activity of Evusheld and viral reduction. x-axis: neutralization activity of Evusheld; y-axis: median viral load reduction compared with untreated profiles at day 5 (left) and day 7 (right) after treatment initiation. The dotted lines represent, for each variant, the predicted viral reduction following the increase in neutralization activity by Evusheld estimated in our population. Parameters and patient characteristics are sampled from the viral dynamic model (see Methods).