England must launch their grand slam defence without three first-choice forwards – and face question marks over four more.
Joe Launchbury has joined Billy and Mako Vunipola on the sidelines after sustaining a calf injury that will rule him out of at least the Six Nations opener against France on February 4.
The Vunipola brothers are suffering from knee problems but while Billy will struggle to play any role in the tournament, it is hoped that Mako will figure at some point.
Doubts also exist over George Kruis, Chris Robshaw, Dylan Hartley and James Haskell, although it is thought the quartet will be ready for the visit of France to Twickenham.
The biggest concern is over Robshaw, who has aggravated a shoulder issue that will be assessed by Harlequins this week, with England head coach Eddie Jones raising the possibility of surgery.
Kruis has a fractured cheekbone, Haskell has yet to make his comeback from a foot operation for Wasps, while Hartley must prove his fitness if he is to lead England into the Six Nations having served a six-week ban.
“This is the way it is with injuries. As we said in November, it is chance to create some more depth,” Jones said.
“For 2017 we are going to be missing potentially four of the starting pack, but we got through November without seven front-line players. So it’s a great opportunity, exciting.”