Role of human challenge trials (HCTs) in drug development for respiratory syncytial virus (RSV)

Abstract

AbstractHuman challenge trials (HCTs) are powerful in establishing early proof-of-concept for experimental drugs and understanding disease pathogenesis. In this study, we conducted a comprehensive assessment of HCTs to understand the viral load dynamics and symptom score kinetics of respiratory syncytial virus (RSV) to facilitate drug development for RSV. We estimated viral load (VL) and symptom related measures in placebo and relative reduction (RR) of the measures in the experimental drug using a systematic search on double-blind, placebo-controlled RSV HCTs from clinical databases. We used random-effects meta-analysis, except for time to mean peak VL and time to mean peak total symptom score (TSS), where descriptive statistics were summarized. Number of studies varied across measures, from 4 (151 subjects in total) to 7 (247 subjects in total). Overall, treatment reductions of 54% (95% CI: 32% – 76%, I2= 91%) and 76% (95% CI: 68% – 85%, I2= 19%) are observed in mean VL area under curve (AUC) and mean TSS AUC, respectively. In placebo, mean time to mean peak VL/TSS was 6.99/7.09 days (95% CI: 6.24/6.06 – 7.74/8.12 days). In comparison to other viruses in HCTs, peak VL occurs earlier for influenza (1.7 days) and at similar time for SARS-nCoV-2 (7 days), whereas peak TSS occurs earlier for influenza (2.9 days) and later for SARS-nCoV-2 (7.9 days). Our findings will inform researchers on disease course and VL kinetics, critical data needed for designing RSV treatment studies and understanding implications in clinical practice.