About 15 years after the events of Dead Island,[5] the US military are forced to put Los Angeles under a full quarantine restricted zone due to a new and stronger zombie outbreak.
As Los Angeles is being quarantined, six individuals (dubbed “Slayers”) board one of the last evacuation flights out of the city: hustler Bruno, mechanic Carla, retail worker Dani, firefighter-themed stripper Ryan, athlete Amy and stuntman Jacob.
In the confusion, an infected person ends up on board and the military shoots the plane down. The Slayers narrowly survive the crash, but are bitten trying to help some other survivors. They manage to make their way to the home of one of the crash survivors, actress Emma Jaunt, who reluctantly shelters them despite their infection. Sam B, Emma’s ex-boyfriend, arrives at the mansion intending to get Emma out of the city and, revealing he is immune to the infection, the Slayers come to realize that they are immune as well. With the Slayers still intent on getting out of the city, they head to the nearest evacuation center at the Halperin Hotel, but find it overrun with infected. They recover a radio and make contact with Dr. Reuben Reed, a CDC doctor who asks them to come to his safe haven in Santa Monica in order to use their immunity to synthesize a cure. Sam warns the Slayers not to trust Reed.
The Slayers head through the sewers to get to Santa Monica, discovering that the zombie corpses the military have been dumping into the sewers have melded together into a massive, tumor-like growth spreading underneath the city. They are stopped by another group of survivors led by Lola Konradt, who drops the Slayers into a pit full of zombies which temporarily triggers a bestial rage in them which they use to kill all the zombies. The Slayers manage to reach Reed’s haven at the Serling Hotel, where he informs them that the military will not extract them unless they provide proof of immunity, which means using Reed’s testing equipment at the overrun CDC HQ. The Slayers recover the equipment and return to find out that Reed and Konradt are acquaintances. The Slayers are then sent to find Reed’s missing daughter Tisha, who is working with a team of hackers investigating mysterious encrypted data being exchanged by the CDC. Tisha gives the Slayers a way to contact Konradt directly in return for them giving her more time to investigate the CDC.
Konradt tips the Slayers off about a secret lab where Reed was sending other immune subjects. While fighting an infected test subject, the Slayers succumb to their bestial instincts and attack Tisha, who apparently kills them, only for them to be revived by Konradt. She explains that she, her followers and the Slayers are a new type of human dubbed “Numen”, who can assimilate the infection, called the Autophage, while retaining their minds and gain a telepathic hive mind with other Numen. Before leaving, she warns the Slayers that Reed is not actually searching for a cure. The Slayers return to the Serling Hotel to confront Reed, only to find that he has fled with Tisha to a lab on Hollywood Boulevard and that he was responsible for the city-wide Autophage outbreak.
Furious at constantly being lied to, the Slayers gather Emma, Sam and helicopter pilot Patton with the intention of stealing Reed’s helicopter and leaving the city. They reach Hollywood Boulevard, where Sam starts succumbing to the Autophage, his immunity deteriorating. The Slayers go on ahead and confront Reed, who admits that he released the Autophage in the city in order to filter out Numen, explaining that the Autophage is not a plague, but a part of humanity’s DNA that is hard-coded to wipe them all out at a predetermined time; the Numen, who he considers either anomalies or “puppets” of the Autophage, were his only way to find a method to neutralize it. He gives the Slayers a single dose of Autophage cure, and reveals that Tisha also carries the cure in her body as he secretly injected her with Numen blood prior to birth in order to harvest the cure for the rest of her life. Reed succumbs to the Autophage, forcing the Slayers to kill him while Tisha flees.
The Slayers return to Emma, Sam and Patton and administer the cure to Sam, saving his life. The Slayers decide to stay behind in order to find Tisha, as well as help the other survivors trapped in the city. As Emma, Sam and Patton escape the city, Konradt and her followers watch over the Slayers as they fight another horde of zombies.
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