Vunipola faces four months out after knee surgery
Vunipola damaged cartilage in his right knee during Saracens' 41-13 victory over Sale on Saturday and will now miss England's November Tests against Argentina, Australia and Samoa.
Saracens said he had undergone surgery to repair the meniscus in his knee on Sunday.
"For any team to lose a player of the ability of Billy is a blow and he will be missed through the autumn for both Saracens and England," Saracens Director of Rugby Mark McCall said in comments published on the club website.
"It's desperately disappointing for him, considering how hard he has worked during the off-season to get back to full fitness.
"But Billy is a resilient character and he'll have a strong support network around him to get him back on the field in the best possible shape.
"What's now important for Billy is his recovery and we look forward to his return later this season."
England open their 2018 Six Nations campaign against Italy in Rome on February 4, which is less than four and a half months from now.
Vunipola, 24, was playing in only his second match after returning from a shoulder injury that kept him out of the British and Irish Lions' tour of New Zealand.
He injured the same knee against Argentina last November, which kept him on the sidelines for three months.
Harlequins No.8 Jack Clifford had earlier been called into England's training squad to take Vunipola's place.
England's players are training together in Oxford, northwest of London, for three days as they continue their preparations for their November matches.
Agence France-Presse
