There is such a thing as vampire evolution. As the curse is inflicted upon new peoples of new lands, new bloodlines of vampires rise with their own unique characteristics and abilities. In the 1880s, the sadistic outlaw Skinner Sweet becomes the first American Vampire. He wars against other vampires and humans alike throughout American history and only intentionally sires one other of his kind, Pearl Jones who Sweet turns into a vampire in the 1920s.

The series would later jump to a few years later to the mid 30s, and focus on a young Las Vegas police officer by the name of Cashel McCogan (who would later co-star in American Vampire: Survival of the Fittest) as he is thrust into the war that Skinner Sweet waged against the ancient vampire species. Cash would eventually join the Vassals of the Morning Star, a vampire hunting organization after Sweet infects his unborn son, Gus, with his vampiric blood.

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