Actually, Spaniards did penetrate the Continental US. We had them all the way up into central-eastern Oregon, on gold explorations. They also made pretty secure footholds in the Southwestern US areas, and certainly in California... and it was all done fairly early on (1700's for Oregon)
Regards,
I meant 'early' Spaniards. The pox plague that killed most of the indigenous people of Mexico occurred around 1500-1515 or so. Way before any real exploration of the continental US.