Tall first-change Morne Morkel was the pick of the attack with two wickets for 22 runs in seven overs.
South Africa-born Kevin Pietersen, who made a century in the drawn first Test at Lord's, was 17 not out and Ian Bell, whose 199 in the series opener was his Test-best score, was unbeaten on four.
As at Lord's, where England piled up 593 for eight declared in the first innings of the match, South Africa captain Graeme Smith chose to field after winning the toss.
Left-handed openers Andrew Strauss and Alastair Cook made a steady start.
But South Africa had a breakthrough when Cook was given out for 18 by umpire Billy Bowden, caught down the legside by wicket-keeper Mark Boucher off Morkel, when it appeared the ball had brushed the Essex batsman's trousers without hitting the bat.
However, there was no doubt at all about the way 26 for one became 27 for two when, nine balls later Vaughan, who made just two at Lord's, edged a full-length Dale Steyn delivery to Smith at first slip.
It was not the way Vaughan, on his Yorkshire home ground, would have wanted to mark becoming only the second England captain after Michael Atherton to lead the team in 50 Tests.
Pietersen's first two scoring shots were both boundaries off Steyn, a clip off his legs for four followed by a hooked six.
But Pietersen had a scare when he survived an lbw appeal from Steyn.
Strauss, dropped on 23 by third slip AB de Villiers, only managed four more runs before nicking Morkel, bowling from around the wicket, to Boucher shortly before lunch.
England sprang a major surprise by handing a Test debut to former roof tiler Darren Pattinson. The 29-year-old seamer replaced Ryan Sidebottom after his Nottinghamshire colleague was ruled out with a side strain.
Pattinson, born in Grimsby but brought up in Melbourne, didn't make his first-class debut, for Australian state side Victoria, until January last year.
But Pattinson has taken 29 first-class wickets in six matches for Nottinghamshire this season at 20.86 apiece and was recently included in England's provisional squad for the ICC Champions Trophy.