Influenza viruses continue to cause severe morbidity and remain a continuous pandemic threat. Virus challenge studies in animal models are performed during preclinical vaccine development. Improved methods are needed to improve data quality in animal models to reduce both animal stress and the animal numbers. By evaluating automated activity monitors as a tool for Influenza vaccine development, we demonstrate that activity in mice declines after viral challenge and that this reduction in activity can be prevented by vaccination. Notably, the decline in activity precedes weight loss and could thus provide an objective and early endpoint in Influenza virus challenge studies.