Role of human infection challenge studies (HICs) in drug development for respiratory syncytial virus (RSV): systematic review and meta-analysis.

BACKGROUND

Human infection challenge studies (HICs) are powerful in establishing early proof-of-concept for experimental drugs and understanding disease pathogenesis. A comprehensive assessment of HICs will allow to understand the viral load (VL) dynamics and symptom score kinetics of respiratory syncytial virus (RSV) and facilitate drug development for RSV.

METHODS

In this study, we conducted a systematic search of double-blind, placebo-controlled RSV HICs using Biosis Previews, Embase, Ovid MEDLINE, PubMed, ClinicalTrials.gov, and EudraCT from 1990 to August 2023. We estimated VL and symptom related measures in placebo and relative mean reduction (RMR) of the measures in the experimental drug compared to placebo. The primary outcomes are RMR of VL area under curve (AUC) and RMR of total symptom score (TSS) AUC, and the secondary outcomes are mean placebo VL AUC, mean placebo VL at peak, time to mean placebo peak VL, mean placebo TSS AUC, and time to mean placebo peak TSS. We used random-effects meta-analysis, except for time to mean peak VL and time to mean peak TSS, where descriptive statistics were summarised.

FINDINGS

Number of studies varied across measures, from 4 (144 subjects in total) to 7 (247 subjects in total). Overall, relative mean reductions of 54% (95% CI: 32%-76%, I = 91%) and 76% (95% CI: 61%-91%, I = 21%) are observed in VL AUC and TSS AUC, respectively.

INTERPRETATION

Assessment based on our primary outcomes showed, on average, a 54% reduction in VL AUC with significant heterogeneity between these studies. In contrast, the TSS AUC showed a greater average reduction of 76%, with much lower heterogeneity indicating more consistent results across studies for this measure. Our findings inform researchers on disease course and VL kinetics, critical data needed for designing RSV treatment studies and understanding implications in clinical practice.

FUNDING

This study was supported by Pfizer Inc.