That is one of the hang-ups I've been facing: I have a setting based around a plague and I don't have much in the way of a plague. The setting is based strongly on the game Pathologic, which had a vaguely supernatural element to the plague and its source. All I have on the source of the plague is that it comes from the earth beneath/around the city and is supernatural in some way. Looking at my design document (which I hope is the same as what I posted on the forum), it acts in an intelligent manner; I envision that, as a gameplay element, it reacts and adapts to the actions of the players.
The only mechanical element of the plague I have so far is the Infection Index, a scale of 0-100 representing the progress of the infection within the characters. While it is possible for the players to avoid infection, it is difficult to the point that I expect all PCs to be infected eventually.