Spatially Responsive Mass Vaccination Campaigns for Urban Rabies SUMMARY Epidemics of vaccine-preventable zoonotic diseases are ongoing in major urban centers across Latin America and worldwide. Mass vaccination campaigns can prevent and control epidemics of infectious diseases among humans and animals. The realities of mass vaccination efforts, however, often fall short of their promise. In place of high and even vaccination coverage, many campaigns leave spatial 'pockets' of under-vaccinated individuals. Pathogens, taking advantage of these under-vaccinated areas, can persist, diversify, and re-emerge. Modern computational approaches can mitigate geographic inequities through the careful placement of vaccination sites, increasing demand for vaccination. However, increased demand creates long queues for service, an additional barrier to receiving vaccination. The main hypothesis of our study is that participation in mass vaccination campaigns can be significantly increased through spatially responsive vaccination strategies. These strategies have the potential to maximize coverage, reduce spatial heterogeneity, minimize waiting time at vaccination sites, and increase equity in access to immunization in hard-to-reach populations. We test our methods in the context of an ongoing canine rabies epidemic in the city of Arequipa, Peru. In the first aim we compare the coverage and spatial equity of a new vaccination strategy, incorporating spatial optimization and queueing theory, to current practice through a stepped-wedge cluster randomized trial. In the second aim we develop and test data-driven methods to reach underserved populations through mop-up “precision vaccination” campaigns. In the third aim we assess the acceptability, scalability, and transferability of spatially responsive vaccination strategies for local, regional, and national stakeholders. Our work will lead to new principles and practices that bridge operational research and zoonotic disease epidemiology to better guide vaccination programs. It will allow for the design of effective elimination strategies that will take into account access to healthcare and spatial behavior of vaccinators.