As human civilizations flourished, so did infectious disease. Large numbers of people living in close proximity to each other and to animals, often with poor sanitation and nutrition, provided fertile breeding grounds for disease. And new overseas trading routes spread the novel infections far and wide, creating the first global pandemics.

Here’s how five of the world’s worst pandemics finally ended.

Three of the deadliest pandemics in recorded history were caused by a single bacterium, Yersinia pestis, a fatal infection otherwise known as the plague.

The Plague of Justinian arrived in Constantinople, the capital of the Byzantine Empire, in 541 CE. It was carried over the Mediterranean Sea from Egypt, a recently conquered land paying tribute to Emperor Justinian in grain. Plague-ridden fleas hitched a ride on the black rats that snacked on the grain.

The plague decimated Constantinople and spread like wildfire across Europe, Asia, North Africa and Arabia killing an estimated 30 to 50 million people, perhaps half of the world’s population.

“People had no real understanding of how to fight it other than trying to avoid sick people,” says Thomas Mockaitis, a history professor at DePaul University. “As to how the plague ended, the best guess is that the majority of people in a pandemic somehow survive, and those who survive have immunity.”