Returning from a business trip to Hong Kong, Beth Emhoff (Gwyneth Paltrow) has a stopover in Chicago to have a sexual encounter with a previous lover before returning to her family in suburban Minneapolis. At first, she appears to have contracted a cold during her trip. Her six year-old son from a previous marriage, Clark, also becomes symptomatic and is sent home from school. Beth's condition worsens and, two days later, she collapses with severe seizures in her home. Her husband, Mitch (Matt Damon), rushes her to the hospital, but she continues to have seizures and dies of an unknown cause. Because it affects the brain and central nervous system, pathologists attribute it to a meningoencephalitis virus. Mitch returns home and finds that Clark has also died from a similar infection. Mitch is put in isolation but seems to be immune to the disease. He and Jory, his daughter from his previous marriage, attempt to flee the city, but the Wisconsin National Guard has imposed a quarantine and sealed that state's border with Minnesota. They are forced to return home to face decaying social order and rampant looting of stores and homes. Not knowing whether Jory inherited her immunity, Mitch struggles with his frustration with quarantine and his desire to protect her, while trying to come to terms with the knowledge that his wife was cheating on him immediately prior to both her death and that of his stepson.
In Atlanta, representatives of the Department of Homeland Security meet with Dr. Ellis Cheever (Laurence Fishburne) of the Centers for Disease Control and Prevention (CDC) and express fears that the disease is a bioweapon intended to cause terror over the Thanksgiving weekend. Cheever dispatches Dr. Erin Mears (Kate Winslet), an Epidemic Intelligence Service officer, to Minneapolis to begin the investigation. In addition to tracing the outbreak back to Emhoff, Dr. Mears has to negotiate with local bureaucrats initially reluctant to commit resources and organize the public health response. Dr. Mears later becomes infected with the disease. The Minnesota National Guard arrives to quarantine the city, and Dr. Mears is moved to the field medical station she helped set up, where she later dies.
At the CDC, Dr. Ally Hextall (Jennifer Ehle) finds that the virus is a mix of genetic material from pig and bat viruses. Investigations into cures via treatment protocols or vaccines initially stall as scientists can't find a cell culture in which to grow the newly identified Meningoencephalitis Virus One (MEV-1). UCSF professor Dr. Ian Sussman (Elliott Gould) violates orders from Cheever (relayed through Hextall) to destroy his samples and identifies a usable line of bat cells. Hextall then uses this breakthrough to begin to investigate possible vaccines. The virus turns out to spread via fomites with a basic reproduction number of two; that is, each patient infects two more patients on average — increasing to four after the virus mutates, with one in twelve of the population catching the virus, and a 25-30% mortality rate for those infected.
Alan Krumwiede (Jude Law), a conspiracy theorist, posts videos about the disease on his popular blog. In one blog, he appears sick; he later claims that he recovered using a homeopathic cure derived from forsythia. People seeking forsythia overwhelm pharmacies, thereby accelerating the contagion as infected and healthy people congregate. Krumwiede attracts national attention and, during a television interview, undermines Cheever's credibility by correctly pointing out that Cheever had informed friends and family to leave Chicago before the city was quarantined. Cheever is informed that he will be later investigated for leaking that information. It is also later revealed Krumwiede was never sick and was attempting to boost demand on behalf of investors in the companies producing and distributing the homeopathic treatment. He is eventually arrested for conspiracy and securities fraud, but is soon released after his 12 million blog readers donate enough money to pay his bail.
Meanwhile, Dr. Hextall identifies a potential vaccine, using an attenuated virus. To bypass the time it would take to get informed consent under standard human subject research protocols, she follows the precedent of other vaccine researchers and inoculates herself first. She then visits her gravely-ill father in the hospital to expose herself to MEV-1 and tests the vaccine. The successful vaccine's production is rapidly ramped up and the CDC awards vaccinations via a random lottery based on birth dates for one full year until every survivor is vaccinated. Dr. Cheever, whose phone call to his girlfriend warning her to leave Chicago was overheard by the CDC's janitor, Roger (John Hawkes), later gives his own fast-tracked MEV-1 vaccination to the janitor's son. Dr. Hextall places the remaining samples of MEV-1 in cryogenic storage with H1N1 and SARS. The global death toll reached twenty-six million.
Dr. Leonora Orantes (Marion Cotillard), a World Health Organization epidemiologist, travels to Hong Kong to trace the source of MEV-1. She collaborates with Sun Feng (Chin Han) and other local epidemiologists and public health officials; they identify Beth Emhoff as patient zero. As the virus spreads, Feng kidnaps Orantes to use her as leverage to obtain MEV-1 vaccine doses for his village. Orantes spends months living with the villagers until the vaccine is announced. Feng exchanges Orantes for the vaccine doses. At the Hong Kong airport, her colleague casually mentions that the exchanged doses were placebos; upon hearing this, Orantes, who has grown close to the villagers, rushes away to warn them.
In the closing minutes, a flashback explains the source of the virus: a man driving a bulldozer for the company Beth Emhoff works for, collapses a palm tree—in which bats are nesting—a bat flies over a pig pen and drops a chunk of banana into the pig pen, where it is eaten by a pig. This is how MEV-1 came about as a bat-pig hybrid virus. The next day, a group of Chinese chefs collect pigs from the same pen and take them to a casino. One chef is approached and called away from his preparations of the infected piglet, and casually wipes his hands on his apron. The chef later greets and shakes hands with Beth Emhoff, making her patient zero and the origin of the MEV-1 virus.
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