Mako Vunipola and Chris Ashton are replaced by Ben Moon and Jack Nowell in England's starting line-up to take on Wales.
Ellis Genge was removed from training on Thursday, but Steve Borthwick does not think there will be any 'major consequences' for the prop.
Eddie Jones' England have made a flying start to the Six Nations and next up is a trip to Cardiff to face Wales.
Mako Vunipola limped out of England's win over France on Sunday and will miss the rest of the Six Nations with an ankle-ligament injury.
Mako Vunipola limped out of England's win over France on Sunday and will play no part in the remainder of the Six Nations.
Mako Vunipola has a calf injury and has joined his brother, Billy, in being ruled out of England's November internationals.
The unfortunate Billy Vunipola is expected to be out until January after he was injured in Saracens' win over Glasgow Warriors.
The Vunipola brothers, Maro Itoje, Jamie George and Owen Farrell felt the effects of a fiery contest at Scotstoun.
Newcastle Falcons' return to Europe's elite club competition was worth the wait as they beat stunning Toulon at Stade Mayol.
Premiership champions Saracens have tied Billy and Mako Vunipola down to long-term contracts.