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Seraph of the End: Vampire Reign is a dark fantasy manga set in a post-apocalyptic world where a mysterious virus has wiped out most of humanity, sparing only children. In the aftermath, vampires emerge from the shadows to enslave the surviving humans, ruling over them in underground cities as livestock.

The story centers on Yuichiro Hyakuya, a hot-headed orphan who escapes vampire captivity after losing his family to a brutal massacre. Driven by hatred and a desire for revenge, Yuichiro joins the Japanese Imperial Demon Army, a human resistance force that fights vampires using cursed weapons inhabited by demons.