During the original outbreak of the Rage Virus, Don, his wife Alice and four more survivors hide in a barricaded cottage on the outskirts of London. They hear a terrified boy pounding at their door and Alice lets him in. A few minutes later, they discover that the infected have followed the boy. The infected attack and kill most of the survivors, while Don, Alice and the boy are chased upstairs. Don pleads with Alice to leave the boy but she refuses. He abandons them as the infected break into their room by escaping out of the window. After watching his wife being dragged out of sight by the infected, he narrowly escapes on a boat piloted by Jacob, one of the remaining survivors, who falls in the water and is overcome by the infected.
After the infected begin to die of starvation, NATO forces take control of Britain. Twenty-eight weeks after the outbreak, an American force, under the command of Brigadier General Stone, brings in settlers. Among the new arrivals are Don and Alice's children, Tammy and Andy, who were out of the country during the outbreak. They are admitted to District One, a safe zone on the Isle of Dogs, guarded by the US Army. Sergeant Doyle, a Delta Force sniper and his friend, Chief Flynn, a helicopter pilot, are amongst the troops guarding the district. Tammy and Andy are reunited with their father, who was found by the US Army and has become the district's caretaker. In their new flat, Don fabricates a lie about the circumstances surrounding their mother's death.
That night, Andy dreams about forgetting his mother's face, so Tammy and Andy sneak out of the safe zone and return to their former home, where they collect family photographs and other mementos. To his shock, Andy finds Alice alive and seemingly uninfected in a semi-conscious, delirious state. The three are soon discovered by soldiers and taken back to District One. Alice is taken to a quarantine room, where she is tested and found to be an asymptomatic carrier of the rage virus. Don makes an unauthorized visit to Alice in her isolation cell, begging her to forgive him. She accepts his apology and tells him she loves him, prompting him to kiss her, unaware she is an infected. Don transforms, brutally beats her to death and goes on a rampage, infecting and killing thousands of innocents in the way.
General Stone orders the building to be quarantined and orders a Code Red alert in District One. Civilians are herded into safe rooms while the soldiers search for infected but despite the precautions, Don breaks into a room full of people and starts a domino effect of rapid infection. The crowd, with half its members infected, breaks out of the safe room and into the streets. Scarlet, a US Army medical officer, rescues Tammy and Andy as the soldiers in District One are ordered to shoot indiscriminately. Doyle, unable to bring himself to comply with the order, abandons his post and escapes with Scarlet, Tammy, Andy and several others through the Greenwich Foot Tunnel. Stone orders District One to be firebombed but large numbers of the infected, including Don, escape the bombardment. After escaping with a survivor named Sam, the only survivor of a sniper attack that killed most of the group, Scarlet informs Doyle that the children might hold the key to a cure because of their genetic make up and must be protected.
Flynn arrives by helicopter to pick up Doyle but refuses to take anyone else, as they would be shot down for carrying people who might be infected. However, a desperate Sam attempts to leap onto the helicopter, and is infected and falls, which forces Flynn to abandon the four. Flynn contacts Doyle by radio and tells him to leave the civilians and head to Wembley Stadium. Doyle ignores his instructions and escorts Andy, Tammy and Scarlet to Wembley. They break into an abandoned Volvo V70 to escape nerve gas released to kill the infected but are unable to start the car while soldiers with flamethrowers draw near. Doyle exits the car and sacrifices himself by push starting the car and is burned alive. Scarlet escapes an Apache gunship and drives Tammy and Andy into the London Underground, where the trio continues on foot. Don ambushes and kills Scarlet, then bites Andy.
Tammy shoots Don before he can kill Andy, who remains symptom-free but an unknown carrier of the Rage virus. They continue to the stadium and are picked up by a reluctant Flynn, who flies them across the English Channel to France, as instructed by Doyle. Twenty-eight days later, a French-accented voice requesting help is heard from the radio in Flynn's abandoned helicopter. A group of the infected are then seen running through a tunnel that, as they emerge into the open, is revealed to be the exit of the Paris Mรฉtro Trocadรฉro Station with a view across the Seine to the nearby Eiffel Tower, indicating that the virus has spread to Continental Europe.
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