At Horizon Labs, everyone is working fast on the spider-sense jammers and vaccinations before reports come in about people physically mutating into human-sized spiders. Even non-powered heroes like Hawkeye are mutating. The only one left in the open is Mary Jane. Meanwhile, Adriana Soria ventures out to meet her subjects. She then reflects on her history leading up to this point, especially when she was defeated by Spider-Man and Captain America. And recently, she had captured Cap and had him mutated into Spider-King, to stand as her consort. On cue, Spider-King has returned. Unknown to her, it is actually Venom in disguise. And Soria comments that there is no cure for the spider-virus, which Jackal fully confirms.
At Our Lady of Saints Church, various spider mutates approach Anti-Venom to cure them. Rejoicing that he is needed, Anti-Venom agrees to cure them.
With New York less than 20 minutes away from full contamination, Mayor Jameson grows more restless by the minute that Horizon nor Mister Fantastic can cure everyone. Therefore, he leaves for the Emergency Command Center for a "package", ignoring everyone's insistence that he must be quarantined.
While Spidey is fleeing all the mutates, Madame Web tells him to assist Jameson, whose motorcade is under attack. However, Jameson refuses to be saved by Spidey again and decides to intervene personally. But unknown to Jameson, since he's infected, Soria can telepathically influence him. Venom thinks to act to stop her from using Jameson to spread her plague when everyone is informed about Anti-Venom an his curing touch. Venom volunteers to go after Anti-Venom, knowing that only he can save Spider-Island. He relays this news to Project Rebirth 2.0, who inform Mister Fantastic.
At the NYC Emergency Command Center, Jameson approaches Alistaire Smythe, the Spider-Slayer, for help. Smythe finds it a joke that Jameson would come to him after wasting his father's life hunting Spider-Man. He then comments on the irony that Jameson has become a Spider-Man. Soria takes the opportunity to influence Jameson, appearing to him as his wife, convincing him that she lied about who not to blame. Jameson then sprouts larger teeth.
Elsewhere on Spider-Island, Heroes for Hire is taxed to capacity holding off the spiders from reaching the jammer; Flash battles with the Venom symbiote as to not destroy Anti-Venom; and Mary Jane finally gets spider powers. By then, everyone on the island is infected. Luckily, Venom brings in Anti-Venom. However, Mister Fantastic tells him that they will need his entire suit to cure the infection.
Back at the ECC, Jameson attempts to attack Smythe, though Spidey tries to restrain him. Out of terror, Smythe claims that his Spider-Slayers can stop the epidemic. Two Mandroid move in to separate both Spidey and Jameson but in doing so, Jameson takes a chunk out of Smythe's neck.
