Who are some prominent actors/actresses who have never been in a sequel? “Never been in a sequel” in this case meaning they have never reprised a role in a separate movie.
As far as I know John Cusack has never been in a sequel, though War, Inc. was damn near a sequel to Grosse Pointe Blank.
Helen Mirren, according to the definition in the OP (she was in National Treasure: Book of Secrets, but wasn’t reprising a role).
Of course, many Golden Age actors never reprised a role. Humphrey Bogart, Cary Grant (technically, he reprised his role in Topper Takes a Trip, but that was just reusing footage from the earlier film), and Clark Gable come to mind, and I’m sure there are dozens of others.
Actually, I’d guess a LOT of Golden Age Hollywood stars never made a sequel. Sequels are much more common now, and many more movies are made in the HOPE that they’ll be successful enough to spawn sequels.
John Wayne made a seqel to "True Grit, of course, but that was later in his career.
If we’re sticking to current stars, I can’t think of any sequels Meryl Streep has appeared in.
W.C. Fields, Groucho Marx (though all their characters had similarities), Mae West, Burt Lancaster, Fred Astaire, Gene Kelly, etc. (not counting when they appeared as themselves).
More recently, Adam Sandler, Heath Ledger, Jake Gyllenhaal, Kenneth Branagh, and Richard Pryor.
It doesn’t appear that Kevin Costner has made any sequels either (“Field of Dreams 2” is not a sequel to the Costner original- it’s a satirical short that DOES feature Costner as an Iowa farmer!).