Exciting ideas in an intriguing thread. I am hype!
I'm not sure how much of the original novel I'd follow myself, but here are some minor ideas to build up on what you've all come up with:
-Backstory: Van Helsing is Quincey's estranged mentor. A younger Van Helsing receives the Vampire Killer from an aged Richter, who tells Van Helsing to seek out the Belmont clan's blood relatives and pass the whip to them. Van Helsing finds Quincey in America and enlightens him to his heritage. Quincey trains under VH but they later have a falling out, possibly over the price that must come with unlocking the VK's power. Quincey becomes an aimless adventurer over the years only to meet his mentor again in London during the Lucy Westenra incident. His grief over losing her compels him to embrace his fate.
-A female Lecarde would be a supporting character. She was Van Helsing's apprentice at the the time they found Quincey and they trained together under him. She has an unrequited love for Quincey (who merely sees her as a good friend), made all the worse by the fact that if she unlocks the VK's power for him, she'll have basically killed him.
-Some bosses would be taken from Bloodlines, POR, and OOE. I'd use Queen Moss, Dagon, and Blackmore for starters.
-You can go to Wygol Village during the game's Transylvania segment. One of the residents is an old woman heavily implied to be Shanoa (who probably tells Quincey "You remind me of someone I knew."). She'll probably give you quests and advice or some such.
-Finish the game and you'll be able to play as Van Helsing. Not sure what he'd be like yet.
-The game would be dedicated to Bram Stoker, and say as much in the end creds.
This is how I would end the game.
I was waiting for someone to bring this up amd I'd definitely use it. As well as an abbreviated version of Quincey's last words in the novel, "It was worth this to die. Look... the curse has passed away."