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Abstract This paper describes Epihiper, a state-of-the-art, high performance computational modeling framework for epidemic science. The Epihiper modeling framework supports custom disease models, and can simulate epidemics over dynamic, large-scale networks while supporting modulation of the epidemic evolution through a set of user-programmable interventions. The nodes and edges of the social-contact network have customizable sets of static and dynamic attributes which allow the user to specify intervention target sets at a very fine-grained level; these also permit the network to be updated in response to nonpharmaceutical interventions, such as school closures. The execution of interventions is governed by trigger conditions, which are Boolean expressions formed using any of Epihiper’s primitives (e.g. the current time, transmissibility) and user-defined sets (e.g. people with work activities). Rich expressiveness, extensibility, and high-performance computing responsiveness were central design goals to ensure that the framework could effectively target realistic scenarios at the scale and detail required to support the large computational designs needed by state and federal public health policymakers in their efforts to plan and respond in the event of epidemics. The modeling framework has been used to support the CDC Scenario Modeling Hub for COVID-19 response, and was a part of a hybrid high-performance cloud system that was nominated as a finalist for the 2021 ACM Gordon Bell Special Prize for high performance computing-based COVID-19 Research.