Plague of Justinian
The Plague of Justinian took place all the way back in the year 541-542. At the time, people were living in urban areas alongside animals, which is typically how the disease starts and spreads. This unsanitary lifestyle attracted many diseases, but it is believed that the Plague of Justinian killed about half of Europe’s population at the time (about 50 million people).
This woodblock print from Germany in the late 15th Century is meant to show doctors how to lance a bubo, which was thought to be how to get rid of the Plague. Source: Österreichische Nationalbibliothek
It severely affected the Byzantine Empire, specifically its capital, Constantinople, where the disease wiped out a quarter of the population. It also spread to the Sasanian Empire around the entire Mediterranean Sea. The ports were a perfect breeding location for the disease, and rats carrying fleas with the Plague were moved on merchant ships- ultimately spreading the disease to more locations.