London - England were dealt a further injury blow ahead of the autumn internationals on Wednesday when Premiership club Saracens confirmed prop Mako Vunipola would be out of action for about six weeks.
Lock Nick Isiekwe has been ruled out for two months due to an ankle injury as problems continue to mount for England coach Eddie Jones.
Mako Vunipola, 27, becomes England's fourth loosehead missing -- Joe Marler has retired from Test rugby, while Leicester's Ellis Genge, Bath's Beno Obano and Wasps player Matt Mullan are all sidelined with long-term knee trouble.
"Mako's got a calf injury, so it looks like it's going to be around six weeks," said Saracens' rugby director Mark McCall. "It's a tear in his calf, it doesn't require surgery.
"Nick (Isiekwe) will be around eight weeks, it's a syndesmosis injury of his ankle. That doesn't require surgery either, and it will be eight weeks."
Jones, set to name his squad on Thursday, will be forced to hand someone a full debut in the first Test, against South Africa at Twickenham on November 3.
Exeter Chiefs' Alec Hepburn has one cap as a replacement, while his clubmate Ben Moon and Gloucester's Val Rapava Ruskin will now be England's other main options at loosehead prop.
Mako Vunipola and Isiekwe join Genge, Obano, Mullan, Joe Launchbury, Jonny Hill, Billy Vunipola, Sam Simmonds, Jack Willis and Chris Robshaw as England's sidelined forwards.
Dan Robson, Jonathan Joseph, Anthony Watson and Marland Yarde are all missing from the back-line, with Ben Te'o still a doubt despite working his way back to fitness.
And Wasps number eight Nathan Hughes faces a possible suspension.
After the South Africa match, England play New Zealand, Japan and Australia.