Harlequins prop Joe Marler and Exeter flanker Tom Johnson will make their England debuts in Saturday's first Test against South Africa in Durban.
Head coach Stuart Lancaster has also opted to move Ben Foden to the wing to replace the injured David Strettle with Harlequins' Mike Brown coming in at full-back.
Ben Youngs is preferred at scrum-half to Lee Dickson and will partner Owen Farrell, who moves back to number 10 after starting at inside centre in the recent Barbarians match.
Dickson will have to make do with a place on the replacements' bench along with fit-again Leicester fly-half Toby Flood, who has been out for the past month with groin and ankle injuries.
Scrum-half Danny Care, back in the squad after being overlooked for the Six Nations due to a string of off-field incidents, must bide his time before a recall while flanker James Haskell, back in contention for the first time since the World Cup, also sits the game out after only linking up with the squad this week.
Marler, 21, is given his opportunity at loosehead after an outstanding season for the Aviva Premiership champions. Alex Corbisiero, who held that position throughout the Six Nations, has been held back in training by a knee injury this week after recovering from a biceps operation.
Johnson, 29, gets his chance with Leicester's Tom Croft missing the three-Test tour through injury.
Another uncapped player, London Irish centre Jonathan Joseph, is also among the substitutes.
England team to face South Africa: M Brown (Harlequins); C Ashton (Northampton), M Tuilagi (Leicester), B Barritt (Saracens), B Foden (Northampton); O Farrell (Saracens), B Youngs (Leicester); J Marler (Harlequins), D Hartley (Northampton), D Cole (Leicester), M Botha (Saracens), G Parling (Leicester), T Johnson (Exeter), C Robshaw (Harlequins, capt), B Morgan (Scarlets).
Replacements: L Mears (Bath), P Doran Jones (Northampton), T Palmer (Stade Francais), P Dowson (Northampton), L Dickson (Northampton), T Flood (Leicester), J Joseph (London Irish).