Uprising starts with Claire Redfield entering the Raccoon City Police Station. In the main lobby, she is confronted by the game's first zombie which is quickly dispatched by Leon S. Kennedy as he enters the police station soon after; this is Leon and Claire's first meeting as opposed to the original game's diner meeting. Upon inspecting the police station, Leon and Claire happen upon Sherry Birkin, who runs away shortly after she sees them. After solving several puzzles in the police station, including talking to police chief Brian Irons and then fighting a mutated William Birkin and then fighting a "G" parasite that burst from Irons' chest after that, Leon and Claire find themselves down in the sewers where they must operate two doors at the same time in order to open a route to a tram. After this is completed and the tram is activated, Claire then must go to find Sherry who is in an upstairs room. When Claire finds Sherry, she runs away again, insisting that she must find her father, William Birkin. While looking for Sherry, Claire returns to the room that leads to the tram where she meets Annette Birkin, and finds out more about the G-virus and that William injected himself with it. At this point, Claire and Annette hear a scream and Annette pleads with Claire to find her daughter and Claire then begins her search again for Sherry. She finds her in a bathroom in the police station where Sherry tells Claire that her stomach hurts and that her father is not her father anymore, but a monster. Claire then takes Sherry to the tram where they travel with Leon to the lab. After placing Sherry in a safe room, Leon and Claire begin searching for a cure for her. After finding a vaccine cartridge and making the base vaccine, Claire must find Annette in a power room where Annette shows Claire the G sample and Claire tells Annette about Sherry being hurt. At this point, the mutated William makes another appearance and badly injures Annette; he then leaves without fighting Claire. Annette tells Claire about the vaccine and hands her a file on the production of the vaccine, along with the "G" sample. With the base vaccine and the "G" sample, Claire is able to create the vaccine and administer it to Sherry after making it back on the tram which has now been set to take them to the outskirts of town. Just when they think it's finally over, Leon gets locked into another car of the tram while the mutated William attacks Claire and Sherry. Once William is dispatched; Leon, Claire, and Sherry leave the tram and the game ends with Claire still searching for her brother.

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