You know I just got stormed in on Monday (dang you Sandy!) so I played a couple of Solo games... which is a bit rare for me unless I'm playtesting one of my own games but I was just that bored.
So I fought Spite with Wraith, Argent Adept, Mr. Fixer and Visionary and I figured out what is needed to defeat him. In my game the thing that really slowed him down was Twist the Ether reducing his damage by 1 and Argent Adept helping Wraith recycle her Throat Jab to reduce his damage to zero.
So if I was going to assemble a 4 player "dream team" against Spite I would go with:
Legacy since he can reduce damage to himself and re-direct damage to himself. I consider him the best "tank" in the game. By reducing damage, you reduce healing for Spite.
Bunker reduces damage to himself and can save up for one big mega blast if the game slows down enough. Also lots of victim rescues require discarding cards... and bunker has a big hand.
Visionary for Twiste the Ether, Suggestion, Telekinetic Cocoon (immune to damage is good), Demoralization (triggers his first damage prevention) and situational deck control.
Lastly you need Damage + Dodge...
Wraith has Stealth and Razor Ordinance
Fixer has Driving Mantis + Monkey Wrench (this combo stuck with him through the game)
Nightmist: Damage Prevention, Damage Dealing but best of all... she can stop him from playing cards.
Tachyon: Lots of drawing, frequent damage dealing and dodging or counter attacking. Lightspeed Barrages for 10+ damage are nice too.
Tempest: because he does it all... damage prevention, healing, damage, trash recycling, cooking, cleaning, taxes and fish translation.
As for Spite himself... he is never gonna flip his deck... he just needs to get all his drugs out and bam, the game really starts in earnest. So depending on how crazy you are then you want it to happen early (so you dont need to worry about victims and ups an downs) or late (so you can really chip away at him and rescue everyone). My technique was damage reduction, supression and rescue...
Victims
Lost Child: Easiest to save... since H is hopefully 4, so 3 damage can be reduced to 2 or 1 by the teams resident tank.
Innocent Bystander: Also easy if you are drawing those cards efficiently.
Good Samaritan: Unless you are trying to get him to flip asap, sorry samaritan.
Potential Sidekick: I honestly think they struck a good balance with this character... he really is worth keeping around as a sidekick SOMETIMES. And it HURTS when he dies. Situational, but for sure if are preventing damage or drawing from spite this turn.
Drugs
Compound IX: this is a weird one but Tachyon would love this card... she rarely uses powers but she would just to get those bursts out.
Demons Kiss: shut it down early with damage reduction like Twist the Ether.
Compound Upsilon: great to bounce back cards like Bloody Knuckles that would hurt the hero. Otherwise it makes it into a slow wrestling match and bosts his damage... in my opinion one of the worst drugs to draw early.
Compound Omicron: the FIRST time he would be dealt damage, reduce it by 2. Auto start of turn damage is great, or one shots will also get it out of the way while dealing a few points.
Mynd Phyre: hopefully the least troublesome card... like a weaker Demons Kiss.