Objectives: Respiratory syncytial virus (RSV) is a common respiratory illness with more severe outcomes in vulnerable populations such as in children, elderly, and immunocompromised patients1. Each year, RSV is responsible for more than 80% of lower respiratory tract infections (LRTIs) in infants less than 1 year of age2 and is the cause of over 3.6 million hospitalizations and 100,000 deaths in children under 5 years of age3. Despite success in challenge studies, in which healthy adult volunteers are experimentally infected with RSV and treated after testing positive, most novel RSV antivirals have not progressed to demonstrate clinical efficacy in patients. Only one antiviral is currently approved for the treatment of symptomatic RSV patients, with limited utilization due to nonspecific activity, high costs, and toxicity4. Thus, there remains a need for effective and affordable RSV treatment options. The complex dynamics of viral infections and antiviral intervention, including the corresponding immune response and heterogeneity in the patient response to treatment, require a quantitative systems pharmacology (QSP) approach. Overall, this QSP model can be used to predict the impact of therapeutic intervention on RSV dynamics in different patient populations, potentially aiding in the clinical development of novel therapeutics.
Methods: We have continued to develop and apply a mathematical model of RSV viral dynamics and antiviral intervention5,6. Key underlying differences in viral dynamics between healthy adults (i.e., volunteers in challenge studies) and pediatric patients were quantified by calculating peak viral load and post-peak viral load slopes across longitudinal studies. Preclinical and clinical virology and pharmacokinetic data, including challenge studies and pediatric patient data for RSV F-protein7 and N-protein8,9 inhibitors, were leveraged to create multiple virtual populations describing viral dynamics in healthy adults and pediatric patients in both placebo and active treatment groups. The model was used to simulate virological efficacy in healthy adults and in pediatric patients for RSV antiviral interventions initiated at different times.
Results: Pediatric patients were observed to have a higher peak viral load and slower viral clearance than in otherwise healthy adults. To capture these differences, separate healthy adult and pediatric virtual populations were constructed to represent viral load dynamics in associated randomized placebo-controlled studies7,8,9. Using these virtual populations, we projected that pediatric patients will be less sensitive to how quickly treatment is initiated relative to symptom onset compared to healthy adults, in whom early intervention is predicted to be key for observing high viral load reductions.
Conclusions: Using this QSP model of RSV dynamics, we predict that pediatric RSV patients may have a wider treatment window for reducing viral load through antiviral intervention compared to otherwise healthy adults. In general, this RSV viral dynamics model can support and accelerate the development of novel antiviral compounds and could be used to support dose and dose regimen decisions for clinical efficacy trials, including in special populations.
Citations: [1] Kaler et al, Cureus (2023). [2] Piedimonte et al. Cleve Clin J Med. (2015). [3] Li et al. Lancet (2022). [4] Sun et al. Viruses (2013). [5] González-Parra, Dobrovolny, J. Math. Biol. (2019). [6] Link et. ACoP Poster (2023). [7] DeVincenzo et al. Antimicrob. Agents Chemother. (2020). [8] Ahmad et al. NEJM (2022). [9] Enanta RSVPEDS Topline Data Results Presentation (2024).
