One Health genomic epidemiology reveals cryptic transmission and surveillance gaps in a decade-long urban rabies epidemic in Arequipa, Peru

Persistent local foci remain a major barrier to eliminating dog-mediated rabies, yet the processes sustaining transmission at micro-scales, particularly within complex urban systems, remain poorly understood. We apply an integrated One Health genomic epidemiology framework to reconstruct a decade-long rabies virus (RABV) epidemic in Arequipa, Peru. Combining 133 newly generated whole genomes with existing data, we assembled the most comprehensive canine RABV dataset in Latin America and used whole-genome-informed phylogenetic, phylodynamic and landscape analyses to trace the epidemic from its first detection in 2015. Transmission was dominated by a single lineage, estimated to have been introduced around 2012, which circulated for approximately three years before detection. We estimate that only 1-2% of infections are routinely detected, revealing extensive cryptic transmission and highlighting the limitations of case-based metrics for verifying disease freedom. Although additional regional and transboundary introductions were identified, only one resulted in sustained transmission. Within Arequipa city, transmission was highly structured, concentrated in densely populated and socioeconomically deprived areas, and shaped by urban connectivity. Roads and dry water channels facilitated spread, while rivers acted as partial barriers. Our findings demonstrate that rabies persistence reflects interacting processes across spatial scales, from regional introductions to highly structured urban transmission. They highlight the importance of genomic-informed, spatially targeted surveillance and control strategies to identify and address persistent transmission foci and accelerate progress towards elimination.