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A century ago, nonpharmaceutical interventions such as school closings, restrictions on large gatherings, and isolation and quarantine were the centerpiece of the response to the Spanish Flu. Yet, even though its cause was unknown and the science of vaccine development was in its infancy, considerable enthusiasm also existed for using vaccines to prevent its spread. This desire far exceeded the scientific knowledge and technological capabilities of the time.Beginning in the early 1930s, however, advances in virology and influenza vaccine development reshaped the relative priority given to biomedical approaches in epidemic response over traditional public health activities. Today, the large-scale implementation of nonpharmaceutical interventions akin to the response to the Spanish Flu would face enormous legal, ethical, and political challenges, but the enthusiasm for vaccines and other biomedical interventions that was emerging in 1918 has flourished.The Spanish Flu functioned as an inflection point in the history of epidemic responses, a critical moment in the long transition from approaches dominated by traditional public health activities to those in which biomedical interventions are viewed as the most potent and promising tools in the epidemic response arsenal.