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Background: Animal models of respiratory viral infections are essential for investigating disease pathogenesis and the efficacy of antivirals and vaccine candidates. A major limitation in the research of respiratory diseases in animal models is correlating clinically relevant changes in pulmonary physiology with cellular and molecular mechanistic studies. Few animal models have captured and correlated physiologic changes in lung function and immune response within same experiment, which is critical given the heterogeneous nature of lung disease due to viral infections. In ventilated human patients, pulmonary physiology testing can be used to not only capture oxygenation, ventilation, but also pulmonary mechanics to yield quantitative measures of lung function and scalar tracings of flow-volume and pressure-volume loops. Application of this protocol during mechanical ventilation in non-human (NHP) models would represent a major advance in respiratory viral disease research., Methods: We have applied and optimized a human pulmonary physiology testing protocol to ventilated pigtail macaques (Macaca nemestrina) at baseline and 5 days after influenza A (IAV) viral inoculation., Results: The NHPs manifested clinical disease with hypothermia and loss of body weight. Declines in lung function were striking with a 66%-81% decline in P/F ratio, a measure of oxygenation reflecting the ratio of partial pressure of oxygen in arterial blood (PaO 2 ) to the fraction of inspiratory oxygen concentration (FiO 2 ). There was also a 16%-45% decline in lung compliance., Conclusion: We describe a new approach to performing pulmonary physiology testing protocol in non-human primates to better capture quantitative correlates of respiratory disease and demonstrate protection by therapeutics and vaccines., (© 2024 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)