The plague of 1348 is the most significant because

The plague of 1348 was called the Black Death or, the Bubonic Plague was the most significant because it killed more than 60% of the whole population of Europe. It was carried by rats and when the rats went into boats, it spread onto the sailors and then on everything that was on the boat, spreading it very fast. Hope I helped! 
~Cher Bear~

Ibelieve the answer is d