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The main character of Prototype 2 is Sergeant James Heller, a man who blames the deaths of his family on Alex Mercer. After surviving a suicide mission and being transformed into the virus by Alex Mercer, Heller is looking to kill Mercer, who acts as the game's main antagonist. Mercer's motives are unclear, but unlike the first game he is not committed to stopping the virus, but seems to be spreading it.
After the events of the first game, Manhattan recovered from the initial outbreak and everyone thought that the now named Mercer Virus was eradicaded. 14 months after Prototype, Manhattan has been quarantined again, due to a second outbreak, one far worse than the first one, and blocked off from the other boroughs of New York City, which has been renamed New York Zero (NYZ). The boroughs of New York have been divided into three zones, the Red, Yellow, and Green Zone.