A phylogeny-informed mathematical modeling of HPAI H5N1 transmission dynamics and effectiveness of control measures.

Highly pathogenic avian influenza (HPAI) H5N1 continues to pose a zoonotic risk due to its transmission among wild birds and domestic poultry, with sporadic spillover events to humans. Phylogenetic and surveillance studies indicate that such spillover is driven mainly by interactions among avian hosts rather than by sustained human to human transmission. However, many existing models examine these host groups separately, which limits the understanding of how cross-species interactions influence the spillover risk. To address this gap, we develop a mechanistic model that describes the transmission dynamics within and between wild birds, domestic birds, and humans. Using this framework, reproduction thresholds are derived for each host group, and sensitivity analysis is performed to identify parameters that most strongly influenced the transmission. Numerical simulations examine the effects of inter species interactions on human HPAI H5N1 infection and assess the performance of different control measures. Simulation results show that vaccination with high efficacy and sufficient coverage reduces reproduction thresholds across host groups and decreases human infection, while reduced contact between birds and humans further limits spillover risk. An optimal control formulation is used to evaluate intervention strategies and the results indicate that the combined implementation of environmental sanitation and targeted poultry culling leads to the greatest reduction in transmission and a lower likelihood of human infection. These findings clarify how cross-species interactions shape zoonotic risk and provide a theoretical basis for evaluating control strategies in multi-host systems.