Maria Ōsawa and Minoru Minorikawa are dispatched to Shanghai from Japan, two years after the events of 428: Fūsa Sareta Shibuya de, to cover the upcoming International Anti-Terrorism Conference in the city with various world leaders coming to attend the meeting. Canaan, a Middle Eastern teenaged mercenary, was in the city as well after meeting with the unknown female contact with information that her rival Alphard was captured and secretly detained in Karachi, Pakistan by covert operators of the CIA's Special Activities Division. When Maria comes to see an unknown man dead with the Ua virus, Canaan saves her from being assassinated by masked gunmen before she defeats the rest of them without alerting and panicking the public with heightened senses in synesthesia. Meanwhile, the CIA's SAD convoy comes under attack from an IED ambush while transporting Alphard in their custody.

Liang Ji and Cummings led an airbone attack against the CIA SAD convoy consisting of air-to-surface-missiles and GPMG bursts in order to free Alphard from their custody. Minoru, in a flashback, remembers that his superiors requested him to train Maria in order to become a professional photographer after surviving the events in Shibuya. While eating dinner in Shanghai, Minoru and Maria are targeted by an unknown old man who resembled the official Minoru saw on television en route to the city. Canaan arrives on the scene to save the two reporters from the Mini-Uzi-wielding man, before she was targeted for death by the man himself before he dies by electrocution. The two reporters were later kicked out of their hotel room due to the mess created by unknown men. Minoru later contemplated about the mysterious T-shaped purple mark he saw from the old man and a corpse found from the festival he visited a day earlier.

Deciding to take a lead in the T-shaped purple mark Minoru saw recently, he and Maria visited a Japanese-themed bar to ask a woman before he is stopped by the establishment's bartender. Meanwhile, Alphard began to make plans for an unknown event while Liang Qi is irritated over Alphard's ignorances for her to attack Canaan right away. Canaan later was able to visit Maria with the help of her synesthesia-based abilities despite that she and Minoru were forced to stay in a run-down apartment. Maria and Canaan later decide to take a tour around Shanghai, the two of them visiting the Bund Sightseeing Tunnel when Canaan was lured away from the tram to check on a supposed trap before running back to see Maria missing. Canaan fights against a young boy who told her that he is a Borner due to his mysterious ability after being infected with the Ua virus, which in case gave him the ability to hide in narrow passages. Canaan killed him with a well-placed shot in the body to obtain the detonator for the explosive placed on Maria's head after she was restrained.

Canaan remembers why she wanted to take down Alphard while removing the bullet head from her left arm sustained from being shot in the tunnels of the Bund Sightseeing Tunnel. Maria later has PTSD over the events of her detention and rescue by Canaan, not knowing that Canaan is really an armed mercenary and assassin for real and not the girl she knew from years ago. Alphard, with Liang Ji and Cummings, attend a public function dedicated to the upcoming NBCR International Anti-Terrorism Conference with the selection of the Daedala Corporation, a Private military company that has the Chinese government as its major client to assist Chinese security forces in safeguarding diplomats for the upcoming conference with Cummings as the public head of the company. In a public toilet, Canaan confronts Alphard privately with the latter taunting her for her failure to protect Siam from getting killed. Canaan later flees when Alphard fires her FN Five-Seven USG at the sprinklers.

Maria stays with a girl named Yunyun in her personal houseboat a day after she wanders off in an alleyway without Canaan. Yunyun is later summoned by Liang Ji with a mission assigned to her. Maria and Minoru later investigate the T-shaped marks with the assistance of Japanese physicians back in Japan to study them and find out what has caused them for themselves. Canaan later meets Yunyun embarrassingly as part of the latter's mission is to get rid of her. Despite pleas from Maria, Canaan and Yunyun continue to face off against each other unsuccessfully with a plan by Yunyun to kill herself and Canaan with dynamite mounted throughout her entire body before Canaan decides to save the girl out of pity for Maria since she is her only friend. Back in Maria and Minoru's rented apartment room, Yunyun confesses to her true state as a Borner, but without any kind of special abilities granted to her by the Ua virus' infection since it merely gave her two appendixes. Minoru later pays him with money to help her be a double agent to both him and the Snakes as his personal informant.

Minoru later learns of a villages in the Kashmir region, where most of its residents were purposely infected by the Ua virus with a few survivors being dubbed as Borners for having mysterious abilities given to them by the virus. Minoru later meets with Hakko, one of the employees of the bar he visited revealed to the reporter his suspicions that she was a Borner. The NBCR Anti-Terrorism Conference was now underway with armed Daedala PMCs protecting the dignitaries in the Shanghai International Conference Hall with armed policemen of the Chinese Ministry of Public Security. Liang Ji later perpetrates the bombing of the hall's interior after the American President concluded his speech. Canaan and Minoru head to the hall themselves to secure Maria themselves after hearing the bombings. Armed Public Security policemen later confronted Daedala security forces when they, later with Alphard, attacked the officers when they were trying to get to the building's central control room. Maria is detained by Daedala security forces under Liang's instruction to lure Canaan in and kill her. But remembering the words taught to her by Siam in her youth, Alphard shoots Liang to prevent her from further attacking Maria. Meanwhile, all of the dignitaries were in the underground bunker as planned in case of a terrorist attack in order to be eventually infected by the Ua virus.

The American government convenes an emergency meeting after a dignitary dies from a Ua virus infection. Alphard ignores Liang's anger over her qualms of killing Canaan. Kenji Osawa, head of Okashi Pharmaceutical, had planned to send the anti-Ua virus vaccine to Shanghai when he was supposed killed in car bomb. This "event" forced the American military to send in B-2 bombers from Guam to bomb the entire Shanghai International Confernce Hall in order to purge the Ua virus in flames and prevent in from spreading throughout Shanghai. Canaan infiltrates the hall, rescuing Maria after fending off several Daedala security forces impending her progress. Canaan and Natsume worked together to hack the B-2's bombing and let the bombs miss the conference hall to save the dignitaries inside while heavily armed PLA soldiers, possibly Special Operations Forces troopers escorted Kenji Osawa safely at the outskirts of the hall. Alphard and Cummings retreat underground with a handful of Daedala security forces, the former already deciding to abandon Liang Ji to let her fend for herself. When Maria and Canaan emerge outside, Canaan had collapsed due to her exhaustive use of her synesthesia abilities.

Canaan emerged safe after she collapsed, being told by Maria that she was simply tired. Kenji, in a phone conversation with Minoru, further informs him of the Ua virus and how sometimes people can survive from the virus' infection. The American Vice President later has a tapped phone conversation with Alphard, thanking him for the cooperation she had with him in the nature of ensuring "Anti-terrorism" business keeps going for a few more years. During a public concert, Hakko showed off her Borner ability with people having severe headaches without them being aware. It later forced Canaan and Maria to flee as Hakko had nightmares of how she first knew of her ability from being infected with the Ua virus. Minoru later confronts Santana, Hakko's "guardian", over the nature of the Borners and the Ua virus. Canaan and Maria later go on a long cruise with Santana, Minoru and Hakko in a SUV that took them to the desert regions of China. Maria and Canaan later talked about being together and reaffirming their friendship since it helped them over problems they had such as Canaan's inability to see colors from her synesthesia or from Maria having Canaan by her side all the way, straining the two of them in potential danger. Hakko tries to strangle Canaan in her sleep, remarking to the mercenary that it was her fault. The group later encounters Yunyun, traveling on a bicycle.

Canaan and the others arrive at the outskirts of an abandoned village, where Santana reveals to everyone that it had been the staging grounds of the Ua virus when a said infestation would have actually occurred. He later resigns from the CIA in disgust when he learns that CIA operatives had disguised themselves as Centers for Disease Control and Prevention personnel with the Snakes under Alphard in order to tests it effectiveness on the villagers, which resulted in the creation of both the Borners and the Unblooms in an effort to create supersoldiers under the "Flower Garden Plan." Alphard later encounters Santana, telling him that she would head to the "Factory". A Snakes chopper under Liang Ji's control ambushed Canaan when she targeted her by firing rockets, temporarily sealing her in rubble with Alphard encountering the mercenary. When Alphard left, she informed the ex-CIA agent that he needs to tell Canaan her real name. As Canaan was about to get out of the rubble, Alphard tells Santana that Canaan's name was "Despair".

With Santana's assistance, he was able to lead Canaan and the others inside the "Factory". They were ambushed by Unbloom zombies after being inside, different from the Unblooms Santana had rescued personally after leaving the CIA as they have completely lost all human emotions. Hakko later encounters Liang Ji via TV screen and begins to mock her to come after her. When Hakko returns to the chapel-like room to face Liang Ji, she involuntarily kills Santana with the power of her voice when he had been captured and gagged earlier after being separated. Natsume comes to Canaan and Mino's aid after blasting her way into the facility. Maria and Yunyun enter the "Factory" themselves while wearing mascot head costumes before arriving in the flower gardens. However, Natsume enters the area and encounters the two of them. Seeing that Maria and Yunyun may impede her, Natsume draws out her pistol and aims it at them.

Alphard later enters the flower gardens and blocks off Natsume, telling Maria and Yunyun to leave and see Canaan. During the stand off, Alphard reveals that Natsume is actually a secret agent for the Japanese Defense Intelligence Headquarters and was actually trying to obtain data related to the Ua virus. In addition, Alphard wishes to use "Borners" as potential biological weapons and wishes not to be a part of it anymore. A covert American task force known as Task Force 124, made up of various American special forces units, was deployed secretly into Chinese soil from Afghanistan in order to take down the Factory. Canaan fights off the advance of Delta Force operators already in the Factory, allowing Maria and the others to safely retreat without being caught in the crossfire. Alphard and Cummings meet up with Liang Ji, the latter being infuriated at Canaan's presence and at Alphard's refusal to acknowledge her work. Because of this, Alphard and Liang Ji began to fight against each other to the point where Liang Ji takes some pills to look like her. Liang eventually dies after Cummings shoots her in the back. Canaan finds Hakko making love to Santana's body and gives her pills and tells Canaan that she would stay than leave. Canaan safely evacuates after Task Force 124 UH-60 Black Hawk fired rockets to destroy the Factory. The PLA later acknowledges part of Task Force 124's work as part of anti-terrorist operations after the Shanghai incident.

The group is in low spirits in the wake of Hakko and Santana's deaths. Maria, troubled by Canaan's despair, tries to cheer her up, with limited success. The next morning, they find themselves stranded when their car breaks down. Mino volunteers to stay behind to take care of the car while the girls take a train back to Shanghai. However, the train is stopped by the Snakes. While Canaan leaves to investigate, she is struck by a hallucination of Sian, who tells her to see the truth with her own eyes, while a vision of Hakko blames her for everybody's deaths. Meanwhile, Alphard shoots Maria and locks her and Yunyun in a car rigged with a bomb in an effort to get Canaan to fight at her full power. As Canaan and Alphard fight, Alphard continually taunts Canaan by saying she is the resason for Sian's death. Maria, not wanting Canaan to be burdened by her, has Yunyun detach her train car as the bomb counts down.

As the bomb counts down, Yunyun has second thoughts and runs after the detached carriage. The Bomb explodes and Canaan reacts, as what presumably is her "true strength" becomes apparent, she starts to see Alphard as green (signifying fear) Canaan then injures Alphard, and she attempts to escape via helicopter, that shoots into the carrages to cover Alphard's escape. Before Alphard climbs onto her helicopter, Canaan reveals that Maria isn't dead, as she can still feel her kindness, and that she isn't a "light" to Canaan, but a Friend. Meanwhile Yunyun carries an injured Maria away from the burning carrage. As Alphard tries to escape Canaan shoots the Machine Gunner on the helicopter, making him spin the machine gun to fire into the cabin, killing the pilot and critically damaging the helicopter, Before the helicopter crashes into a mountain face, Canaan and Alphard drop back onto the train that then goes into a tunnel.