Gloucester prop Nick Wood, who was to have made his international debut this weekend, has been ruled out after suffering a torn pectoral muscle in training.
He will be replaced by Saracens' Kevin Yates, who gains a first England appearance for almost 10 years.
Yates last featured for his country against Argentina in June 1997, and he breaks John Bentley's England record for the longest wait between caps of nine years and 44 days.
The problems might not end there for England, as it is thought centre Andy Farrell and scrum half Peter Richards are struggling with the stomach virus that has affected several players during the past three days.
England head coach Brian Ashton has confirmed only one team change from the original selection at present, and he will reassess the situation on Saturday morning, but it would be no surprise if Toby Flood replaces Farrell in midfield and Andy Gomarsall takes over from Richards.
A busy 24-hour period has seen Saracens back Dan Scarbrough fly in from England Saxons duty to join the squad as cover, with wing David Strettle still receiving treatment in Johannesburg for his stomach problems.
Strettle is continuing to be monitored, and it looks as though he could follow Wood in playing no further part on the two-Test trip.
And with Wood now sidelined, Bath prop Matt Stevens has also linked up with the squad.
Stevens flew by private jet from Cape Town, and will now provide front-row cover.
Stevens has not played for England since last year's RBS 6 Nations Championship, having returned to action earlier this season after undergoing two shoulder operations.
For Yates, Saturday's game represents a chance he surely thought had gone.
He played in both Tests on the 1997 Argentina tour in Buenos Aires, but then received a six-month Rugby Football Union suspension after being found guilty of biting London Scottish flanker Simon Fenn's ear during a domestic cup game.
Yates always denied the charge, a stance he maintains to this day, and he now arrives back in the England team following stints with New Zealand side Wellington, Sale Sharks and Saracens.
An under-strength England squad faces a colossal task against South Africa after travelling without players from European finalists Leicester, Wasps and Bath.
They have not won away from home since February last year, and Ashton's preparations have suffered one setback after another.