Antiviral drugs are among the few countermeasures available between the emergence of a novel influenza pandemic and the availability of an effective vaccine. The study developed a multiscale transmission model to re-evaluate country-specific antiviral demand and potential mortality impact, addressing outdated assumptions in prior stockpiling guidance. The model explicitly incorporated heterogeneous healthcare-seeking behavior and direct clinical estimates of antiviral transmission risk reduction to project outcomes across multiple pandemic scenarios.
The authors used clinical estimates of how antiviral treatment reduces transmission risk together with empiric variation in healthcare-seeking behavior. These inputs were integrated into a multiscale transmission framework to produce country-level estimates. The approach departs from older stockpile recommendations by accounting for observed behaviors and recent trial-derived measures of antiviral effects on viral load and onward transmission.
Analyses were performed across 186 countries and across four defined pandemic scenarios to capture a wide range of possible epidemic severities and dynamics. The global scope allowed estimation of both demand (size of population-level stockpiles) and public health impact (projected reduction in pandemic deaths) under consistent modeling assumptions.
The model produced comparative projections for two oral antivirals. Due to its transmission-reducing potential, baloxavir marboxil (BXM) was estimated to avert 37% to 68% of mean pandemic deaths in the first epidemic wave. This projected impact is approximately double that estimated for oseltamivir under the same scenarios and assumptions. The authors note, however, that uncertainty in viral load dynamics and measured transmission reduction from clinical trials means BXM's impact could vary; despite this, sensitivity analyses consistently indicated greater effectiveness for BXM relative to oseltamivir.
Projected mean stockpile requirements differed substantially between the two drugs. For BXM, required stockpiles were estimated at 7% to 34% of the population on average. Oseltamivir was projected to require notably larger stockpiles, approximately 28% to 36% of the population. On average, BXM's stockpile needs were 5% to 10% smaller than oseltamivir's in the modeled scenarios, reflecting both its direct clinical effects and transmission-reducing potential.
When drug availability is constrained, the model identified treatment of symptomatic cases as a higher priority than postexposure prophylaxis for maximizing mortality reduction. The authors examined rationing strategies and found that reserving drugs for high-mortality subgroups (for example, older adults) can substantially lower the overall drug demand for BXM. However, such rationing results in higher total pandemic deaths compared with prioritizing broader treatment, highlighting a trade-off between conserving limited supplies and minimizing mortality.
A critical operational finding was the sensitivity of impact to deployment timing. Each week of delay in initiating antiviral distribution was projected to erode the number of averted deaths by up to 3%. This result emphasizes that stockpiles alone are insufficient: rapid distribution infrastructure and timely activation plans are essential to realize the potential public health benefits of antiviral reserves.
The authors explicitly note uncertainty driven by viral load dynamics and the extent of transmission reduction observed in clinical trials, which influence projected benefits for BXM. While sensitivity analyses consistently favored BXM over oseltamivir, the magnitude of impact remains dependent on those biologic and clinical-effect assumptions. The abstract reports that previous stockpiling estimates relied on assumptions now considered untenable in light of the COVID-19 pandemic and more recent trial data.
The study frames antiviral stockpiling as a key measure for pandemic preparedness but underscores that optimal benefit requires selecting drugs with transmission-reducing properties, ensuring adequate but not excessive stockpile sizes, and — critically — building rapid deployment capacity. Policy implications from the modeled scenarios include prioritizing treatment over postexposure prophylaxis when supplies are limited, caution in rationing to subgroups if the goal is to minimize total deaths, and consideration of baloxavir marboxil as a potentially more impactful oral antiviral than oseltamivir in first-wave pandemic mitigation, subject to the uncertainties noted.
The abstract reports that the authors declared no competing interests. The study provides quantitative projections across many countries and scenarios, but detailed model parameters, full sensitivity results, and country-level outputs were not included in the abstract and would require consultation of the full text for comprehensive operational planning and policymaking.