Forwards Courtney Lawes and Jonny Hill have been ruled out of England's Six Nations opener against Scotland on Saturday.
Flanker Lawes is recovering from concussion, while lock Hill has a foot injury.
Lawes' absence adds to England's leadership problems with regular captain Owen Farrell out for the Championship.
Prop Joe Marler has returned to training following Covid-19 isolation.
Lawes, favourite to replace Farrell as captain, sustained the head injury playing for Northampton on 16 January and has not yet passed return to play protocols.
Exeter's Hill is still struggling with a stress fracture to his lower leg.
England are without Farrell, Jonny May and Anthony Watson for the tournament.
Centre Manu Tuilagi and flanker Sam Underhill are likely to be available later in the Six Nations once they have recovered from respective hamstring and concussion issues.
England's team to face Scotland is expected to be announced at 11:30 GMT on Thursday.
More to follow.