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A rearguard action, which started on Saturday evening when South Africa followed on 346 runs in arrears, ended on Monday with the visitors 393 for three in their second innings.
Hashim Amla, playing his first test at Lord's, joined captain Graeme Smith and Neil McKenzie on the honour's board with 104 not out in 342 painstaking minutes
McKenzie, having resumed on 102 also in his maiden test at cricket's world headquarters, was finally out for 138 in the afternoon session following more than nine hours at the crease.
He batted with Smith as a runner in the final stages after straining his right groin. A spokesman for the South Africans said their medical team were hopeful he would be fit for the second test starting at Headingley in Leeds on Friday.
Jacques Kallis, his team's leading batsman, failed again when he was yorked by an inswinger from Ryan Sidebottom for 13 before tea to give England a glimmer of hope.
But Ashwell Prince, who stood firm in South Africa's first innings with 101 in a paltry 247, survived a chance to Alastair Cook at gully off Stuart Broad when he had scored two to keep Amala company until the close.
Vaughan maintained attacking fields and experimented briefly and unsuccessfully with a version of leg theory with James Anderson bowling around the wicket with six fielders on the leg side.
Monty Panesar, who took four wickets in the first innings, bowled a series of deliveries outside the leg-stump searching for some bowlers' rough, which the batsmen were happy to pad away.
The left-armer was unable to produce the flight that might have compensated for the lack of sharp turn and finished the day with none for 116 from 60 overs.
England batsman Andrew Strauss left the field during the post-lunch session to join his wife who is expecting their second child.