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Air conditioning systems can play a positive or negative role in the spread of COVID-19 infection. The importance of sufficient outdoor air changes in buildings was highlighted by the World Health Organization, therefore these should be guaranteed by mechanical ventilation systems or adequate air conditioning systems. The proposed case study concerns the optimal number of outdoor air changes to limit COVID-19 contagion for a school building in Central Italy. The Wells–Riley model is used to assess the risk of airborne infection, while energy consumption is calculated by a dynamic energy simulation software. The scope of the paper offers an innovative method to define the optimal ventilation strategy for the building's HVAC system design to reduce the risk of infection with limited increases in energy consumption and greenhouse gas emissions. Results show that the desirable approach is the one in which the same low value of contagion risk is set in all rooms. This new approach results in significant energy savings, compared to the most common ones (setting the same high outdoor air rates for all rooms) to counteract the risk of infection. Finally, the zero-emission building target is verified by introducing a suitable photovoltaic system to offset pollutant emissions. [ABSTRACT FROM AUTHOR]