Jordan Henderson, Jack Grealish, Raheem Sterling, Mason Mount and Luke Shaw have withdrawn from the England squad ahead of Monday’s World Cup qualifier in San Marino.
The Football Association also confirmed Conor Gallagher, the Chelsea midfielder currently on loan at Crystal Palace, will join the group in its latest squad update.
Gareth Southgate’s side only need to avoid defeat against the minnows in Serravalle to secure their place in next year’s tournament in Qatar.
Henderson and Grealish will not be available after returning to their clubs, Liverpool and Manchester City respectively, for further assessment on injuries.
City forward Sterling is unavailable due to a personal matter, while Chelsea midfielder Mount requires dental surgery and Manchester United left-back Shaw has suffered a concussion.
Gallagher steps up from the Under-21s following his first senior call-up. The 21-year-old has impressed for Palace this term and scored four goals for Patrick Vieira’s side.
He was involved as England Under-21s beat the Czech Republic 3-1 in their latest European qualifier at Turf Moor on Thursday.
Leeds’ Sam Greenwood will take his place in Lee Carsley’s squad ahead of Tuesday’s game in Georgia.
Paul Merson claimed Southgate made a mistake in leaving Gallagher out in the first place.
He said: “Conor Gallagher should be in the England squad and it’s shocked me that Gareth Southgate has snubbed him.
“He’s been one of the best players in the country this season for Crystal Palace and I don’t think he could have done any more to earn a call-up.
“Chelsea loanee Gallagher deserves to be in there and if he hasn’t got a call-up up now I don’t know how he ever will.
“He affects games every single time he plays and he’s completely and utterly on top of his game. I think he’s really unlucky.
“Southgate could have picked him and sent a message to every young English player that if you’re playing well you will get a chance.
“But he hasn’t, and that sends the wrong message for me – especially as people like Declan Rice have pulled out.”