England's Billy Vunipola out of Six Nations
England's number 8 Billy Vunipola (C) is tackled France's flanker Antoine Burban (L) and France's fly-half Jules Plisson (R) on February 1, 2014 at the Stade de France in Saint-Denis - by Thomas Samson
The 21-year-old No8 suffered a sprained right ankle that forced him off before half-time during England's 13-10 win over Ireland at Twickenham on Saturday, with Ben Morgan coming off the bench for the rest of the match.
Vunipola had a scan on Monday which, the RFU said, revealed ligament damage that will make him unavailable for England's remaining matches at home to two-time defending champions Wales on March 9 and away to Italy on March 15.
"It's a blow as Billy has had a good Six Nations but he is young and he will be back," said England coach Stuart Lancaster.
"The encouraging thing is we have got Ben Morgan and other back rows such as Matt Kvesic and Tom Johnson who are all competing for places."
Saracens and England medical staff will now work on a recovery plan for the eight-times capped Vunipola.
However, the family are still set to be represented in the Test squad, with Billy's brother Mako, two years older at 23, currently one of England's reserve props and who came on as a replacement against Ireland.
England's victory on Saturday saw them create a four-way tie at the top of the table involving themselves, Ireland, France and Wales, all of whom have won two out of their opening three matches this Six Nations.
Ireland though have a huge points difference advantage of +42, compared to England's +21, Wales' +6 and France's +1.