Cost-optimal transmission reduction in early pandemic response: a multi-objective health-economic modelling study across 110 countries

Background: Early pandemic responses must balance transmission control against socioeconomic costs but the strategy that minimises total costs and whether it varies by country remain unknown. We analysed country-specific cost-optimal intervention strategies and examined whether national indices could inform response targets. Methods: We fitted mechanistic models to the first year of reported COVID-19 cases in 110 countries and assessed structural identifiability and parameter uncertainty. Multi-objective optimisation identified efficient trade-offs between transmission reduction and infections across 26-, 40-, and 52-week horizons without vaccination. We selected cost-minimising strategies using GDP-scaled intervention costs and infection costs incorporating quarantine and mortality. Excess-cost ratios, defined as the relative cost increase over the optimum, quantified deviations from the cost-minimising strategy. We also examined associations with national socioeconomic and health-system indices. Results: Cost-optimal average transmission reduction ranged from 31.2% to 57.3% across countries. Across the time horizons, the mean excess-cost ratio for 110 countries was 55.2% (median 30.8%). Excess costs increased asymmetrically around the country-specific optimal transmission reduction: a five-percentage-point transmission reduction below the optimum was associated with excess-cost ratios exceeding 400%, compared with 10-80% for an equivalent increase above the optimum. The range of transmission reduction associated with excess-cost ratios below 40% widened 1.47-fold as the horizon increased from 26 to 52 weeks. Among national indices, the Socio-Demographic Index (SDI) and GDP per capita had the largest redundancy indices (0.40 and 0.37, respectively). Conclusions: Under the modelled assumptions, transmission reduction below the country-specific optimum resulted in greater excess costs than reduction above the optimum, highlighting the potential value of precautionary early-response strategies when intervention effectiveness is uncertain. National socioeconomic and health-system indices may provide a broad indication of cost-optimal intervention intensity, although country-specific conditions remain important. These findings provide a quantitative framework for balancing intervention intensity, infection burden, and economic costs across diverse national settings.