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Directly after the events of Quarantine, on a flight from Los Angeles to Nashville, one of the passengers, Ralph Bundt becomes violent and attempts to enter the cockpit, demanding he be let off the plane. Ralph had been bitten by a hamster which is really a lab rat, brought onto the plane by Henry (Josh Cooke) for his school students. Ralph is restrained, but not before he bites one of the flight attendants, Paula, on the face, much to her friend, Jenny's (Mercedes Mason), horror. Disobeying orders, Captain Forrest and his co-pilot Willsy find a jetway operated by a baggage handler Ed Ramirez (Ignacio Serricchio). Everyone escapes the plane, except for the elderly couple Bev Stevens and her paralyzed mute husband Doc Stevens, and the pilots, who try to keep the violent Ralph contained in an aircraft bathroom. However, they learn that they have been locked out of the airport. Soon, armed soldiers and what appear to be CDC scientists surround the terminal. Ed shows them a door that will lead them to tarmac level but it is locked.
One of the passengers, a military medic named Shilah Washington (Noree Victoria), reveals she has a medical kit in her bag in the plane's cargo hold. Jenny, Henry, Ed, Niall, and Preston sneak back into the plane to retrieve it, to find that Ralph has escaped from the bathroom, whereabouts unknown. Preston retrieves Doc and waits outside. They retrieve Shilah's kit and Niall's handgun and try to leave the hold. While in the plane, Jenny is attacked by an infected Captain Forrest and Niall shoots and kills him, but it seems that some of the captain's blood had gotten into Niall's eye. As they are leaving, they find Preston's body, and an infected Bev who tries to attack the group before they escape. When they meet up with the rest of the group, they begin to realize that the infection is probably a form of rabies spread through bites. Doc is bitten on the head by an infected rat and the group decide to lock him and Paula away to prevent further infection. George (Mattie Liptak), an unaccompanied minor, accuses Henry of being responsible for the infection by bringing rats onto the plane. Jenny talks to Henry and asks if George's accusations are true. When Henry tells Jenny that George is just confused, they reconcile, and are then attacked by the escaped Ralph. With the help of Ed and Shilah, Jenny and Henry kill Ralph by strangling him.
A team of four heavily armed officers administer drugs to the group, and release the infected passengers from their confinement. Before she can receive the drugs, an elderly woman named Louise Treadwell, is bitten by her infected cat. Doc, also infected, bites one of the officials. After shooting Doc, the officers and a passenger named Hvorst attempt to evacuate but are shot and killed by personnel outside the doors, leaving Hvorst's partner, Nicca, distraught. Ed drags one surviving officer back inside, and the group hides in a catering truck from the infected. When they reach the catering truck, the passengers realize Niall is infected, and he grabs and attacks his wife Susan, as the rest of the group is shut inside the truck. The group question the wounded officer, who reveals that he does not represent the CDC but rather the Department of Homeland Security's anti-biological terrorism division called Chemical Biological Domestic Terrorism (C.B.D.T.). He tells them about a quarantined building in Los Angeles that housed a lab for a group of bioterrorists and confirms that the drugs are experimental antidotes, which Shilah had strongly suspected. The wounded officer grabs Niall's gun from Henry and kills himself. While in the truck, Ed remembers that the building has an old drainage tunnel beneath them, but is attacked by co-pilot Willsy from the roof of the truck. George pushes a button to raise the truck and Willsy is crushed to death.
With Henry remaining in the truck, the rest of the survivors access the tunnel, though Nicca is attacked and dragged away. Jenny comes face to face with an infected Paula, whom she kills by pushing her off of a high walkway. They reach the engineer's office and start looking for the blueprints of the tunnel, until an infected Niall and Susan attack. Henry reappears and kills them to save the group, while also revealing he has been bitten. George confronts him with suspicious evidence concerning viruses and maps that he found in Henry's briefcase, to which Henry admits to having been a part of the terrorist cell at the apartment building, who have planned a worldwide plague. Ed attempts to grab Henry's gun and Henry shoots and kills him. While administering himself with the antidote, Henry elaborates that he is part of a bioterrorist group that believes the human population needs to be culled in a plague. Henry kidnaps George and plans to use him as a human shield, in case of attack. Jenny tries to stop him, but is hit in the head with his gun.
Shilah and Jenny are then separated and Jenny encounters the infected Preston, but manages to knock him out. Shilah finds Jenny again, but has been bitten already. As Jenny escapes, Shilah allows herself to be attacked by the rest of the infected to give Jenny a better chance of survival. Jenny finds George near the drainage tunnel, where he tells her that Henry's antidote has failed and that Henry is now infected and mutating into a rat-like humanoid. When Jenny climbs down to George, Henry attacks her, causing the night vision goggles fall to the ground in front of George, who puts them on and shoots Henry. A wounded Henry is finally finished off with a steel pipe by Jenny.
Jenny and George crawl through the access tunnel where Jenny slows down slowly. George notices that she has been bitten through the night vision goggles and says he will not leave without her. Jenny tells him to go but he persists and eventually she goes with him but slows down on purpose to give him time as she is already infected and visible signs of rabies are seen. As George makes it out of the access tunnel first and out of the perimeter of the airport and through vertical bars due to his small body, he calls out to Jenny before she appears at the barred exit, full signs of infection seen, red eyes, blood dripping from mouth and all orifices and screams incoherently. George then takes the goggles off before throwing them down, leaving Jenny.
Through the night vision goggles, an infected cat is seen walking past and in the distance to the Luxor Las Vegas.
What bit Ralph, making him violent?
A hamster