I suppose we could invent a fictional pathogen or just say aliens did it for the sake of the scenario but then we'd have to move the thread to ASB.
A novel pathogen is really not ASB
at all. Pathogens jump to humans from animals all the time, for instance, as smallpox is suspected to have done. (Well, honestly there are a lot of theories re: smallpox but it's damned suspicious.) And as mentioned above, in a naïve population smallpox* was
damned deadly. Mutating
Eastern Equine Enchephalitis to transmit directly between people (normally uses mosquitos) and it would be pretty terrifying. Even if you survive it you're probably going to have brain damage. Venezuelan Equine Encephalitis is pretty bad, too. I guess neither works for Eurasia though since they are New-World, but just find a nice zoonosis.
Maybe LCMV? It's spread by mice, kind of like
Hantavirus, so maybe you could model the spread like plague? (Hanta is innately interesting, being a hemorrhagic fever and all, but it's another New-World virus.) Or how about
H5N1 which is also known to cause encephalitis? Just make it a bit worse due to a random mutation- influenzas are notorious for mutating wildly (that's why we have a new vaccine every year).
*I do reserve a certain special and visceral hatred for smallpox and all those who would weaponize it, may they burn in hell. The Soviets produced a strain that was resistant to damned near every possible intervention and didn't form the characteristic pox (they based it on a natural strain that did that) to make it harder to diagnose. Thank God the US disavowed biological warfare long ago. Of course we merely announced that we would reply with nukes, but, heck, that's just the way it goes. If you drop plaguebombs I have no sympathy for you whatsoever. Well, if you irradiate people to death I have no sympathy for you either, but we're sort of stuck in MAD as much as everyone would prefer otherwise. (And the US has an admittedly vague policy on that point, "defensive use only", which is meant to allow pre-emption of others' WMD use in certain circumstances.)