I found Prion really difficult on Mega Brutal. I did it once, couldn't remember how, and tried loads of different strategies before I found one that worked - twice. Please note, I play on my tablet, I don't know how well this strategy will work on Xbox One or other devices.
Here's how I did it:
Modify with the following:
DNA Genes: Catalytic Switch (this was a breakthrough for me in making it work!)
Travel Genes: Aerocyte
Evolution Genes: Patho-Statis
Mutation Genes: Genetic Mimic
Environment Genes: Extremophile
Prion takes a long time to react to new activations, and it's hard to spread around, too. I tried doing lots of transmission first but it didn't work.
Start it in Egypt.
I got the following in this order:
Drug Resistance (DR) 1
Air 1 (I got this next because I got the notification about dry winds across arid landscapes)
Cold Resistance (CR) 1 (DR and CR because the planes would take it into colder countries, and also those with more sophisticated medical research). During this time the first random symptoms started to pop up - I devolved these to get extra points, but mostly so they wouldn't draw attention to the plague.
Water 2 (I found that I didn't need Air 2)
By now, it had been noticed, so the cure work had started.
IMMEDIATELY, I got Genetic Hardening 1 & 2. I think that once you know the cure is coming (ie, when you get the notification that the plague has infected more people than HIV), you should make sure you have 29 free DNA points to get these two.
Now it's been discovered, you need to make it a real hindrance!
Neural Atrophy (NA) 1
Then I let the points build up a bit and get it very near to the whole world being infected, before getting Pulmonary Fibrosis. You shouldn't get this too early, or it sometimes mutates Total Organ Failure (TOF), which ends the game if you get it too early, as everyone dies off before they're all infected.
So I got Pulmonary Fibrosis, and yes - it mutated TOF very soon after. This wasn't just a lucky one off, it happened 3 times running, so it's worth taking this route.
By the time the whole world was infected, I had 155 DNA points built up, and the cure was at 66%. You'll be glad now that you chose Catalytic Switch as you really need those points from popping the blue medical research bubbles!
Genetic Reshuffle (GRes) 1
I got GRes 2 when the cure was up to 75%. Then it was still mounting, and not enough people were dead - so I got GRes 3 and NA3 when it was at 81%.
Then I thought, I'm in trouble. No more GRes, GH or DR to slow it down, and I could see that it was going to reach 100% before everyone was dead. So I devolved Water 2 and CR 2, which gave me 2 more all important DNA points. I've found that if you amass loads of points before everyone's infected, it doesn't always give you anything back when you devolve, you have to wait until you've used up a load before it does.
I got Coma and Paralysis to slow the cure down.
I was still in trouble, though!
I chucked everything I could at it, anything that looked likely to slow it down.
Insanity!!! (Make 'em too mad to work out the cure, right?)
Dysentry (.... and having to rush out of the room every five minutes...)
Finally, the cure stopped increasing at 94% and I was home and dry, exterminating humankind with a total of 15900 points.