The trio have paid the price for last weekend's 20-14 loss to Australia which meant England slipped to fifth place in the International Rugby Board rankings which will determine the seedings for the 2015 World Cup.
Prop Joe Marler will also miss Saturday's match after straining medial ligaments in his knee in the game against the Wallabies.
Back row forwards James Haskell and Ben Morgan have been included in the squad while London Irish centre Jonathan Joseph replaces Sharples.
"We have made some changes this week to freshen up the squad before the challenge of South Africa," coach Stuart Lancaster said in a statement on Tuesday.
"Unfortunately that means one or two players missed out who were in the matchday squad against Australia.
"The changes, however, give opportunities to those who have been pushing hard and we feel will add energy and balance to the team ahead of the significant South African challenge."
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- Joe Marler