Hooker Jamie George, wing Tom Roebuck and centre Ollie Lawrence have been ruled out of Sunday’s match against Argentina as England’s tough autumn stretches the squad.
All three started the 33-19 win over New Zealand last weekend, but George and Lawrence picked up hamstring injuries while Roebuck has a foot problem.
Two other regulars, lock Ollie Chessum and centre Tommy Freeman, are again unavailable after missing the victory over the All Blacks.
Hooker Jamie Blamire, second row Charlie Ewels and uncapped teenage wing Noah Caluori come into the squad as Steve Borthwick’s side target an unbeaten autumn.
Caluori, who was named in England’s initial autumn internationals squad, scored in England A’s win over Spain on Saturday.
Argentina are in London this week after cruising past Wales and then coming back from a big deficit to stun Scotland in Edinburgh last Sunday.
Fly-half George Ford, who masterminded a 2-0 series win in Argentina in the summer, says England will be expecting a tough time against the Pumas.
“I know first-hand from being there in the summer how good a team Argentina are,” Ford told BBC Sport.
“They are an incredible, emotional and passionate team and we will have to make sure we get our prep right for that.”
Meanwhile, full-back Freddie Steward is available for selection despite failing a head injury assessment in the first half against the All Blacks.
The Rugby Football Union says Steward passed both his second and third HIAs, so is cleared to play this weekend.