I think Carl is the safest of everyone; he's the point of view character, the John Connor of the series. The whole story is seen through the eyes of a boy growing up in this horrid world, and what kind of person he'll grow to be. For the same reason, I think Rick is only marginally less safe, for the same reason.
If they're talking mega-major characters other than those two, they'd have to go with the few who are left from the original camp, which would be Glenn, Darrell, and Carol. As for Darrell, even though he's not in the comics (which I haven't read, incidentally), so they wouldn't have to worry about continuity, killing him would be like killing Fonzie - he's the breakout character everyone talks about, so it would be a short-term talking point which would long-term damage the show, so not him. I could see it being either Glenn or Carol, though; I give the edge to Glenn, though, because of the dramatic possibilities it raises, and besides, he and Maggie are just too happy.
Mind you, this is all theory.
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