A panzootic of H5Nx avian influenza viruses has severely affected poultry and wild bird populations resulting in multiple mammalian spillovers, including human infections caused by antigenically distinct and diverse virus clades. The unpredictable nature of spillover events of antigenically drifted and/or reassorted H5Nx viruses hinders our ability to effectively respond retroactively to the heightened risk of human-to-human transmission. Stockpiled strain-specific H5 whole virus-based vaccines provide limited breadth and reduced efficacy. To address this problem, we computationally designed vaccine antigens that induce broad protective immunity. Mice immunised with the DVX-panH5Nx mRNA vaccine candidate generated robust immune responses across A/H5 clades and provided crucial cross-clade protection against lethal H5N1 challenge, including strains that have recently caused human infection. Furthermore, ferrets immunised with DVX-pan-H5Nx demonstrated superior protection and immune breadth when compared to an industry standard inactivated antigen derived from the WHO candidate virus vaccine A/Astrakhan/3212/2020 (H5N8), against a lethal heterologous challenge.