You could always annex them then release them. Catholic nations get an event to return Rome to the Pope - I'd recommend at least considering that (I don't remember the penalties for breaking vassalization but IIRC stab is involved, and I usually prioritize ADM over DIP so the annexation cost is preferable), and if it's right for you, do it then save Rome for the last leg of your conquest. Consider it a valuable lesson in Italian conquests.
As for the Spain issue, always try and kiss up to France and Austria when you're in Italy. France will almost always be eager to help slap the Spanish around, and Austria - unless allied - will at least serve as a deterrent against invasion. They're less likely to help though, due to Distant War. Obviously, losing the -2 Dip Rep will help securing both of them.