England's Vunipola out for three months
The Saracens forward, 24, tore cartilage in his knee during the first half of England's 27-14 victory over Argentina at Twickenham on Saturday and was taken off the pitch on a medical cart.
Defending champions England launch their Six Nations title defence against France at Twickenham on February 4 and play their final game against Ireland in Dublin on March 18.
"Billy's been absolutely fantastic for England over the last 11 months and we wish him a quick recovery," said England head coach Eddie Jones, whose side close the year against Australia next weekend.
"He's a very influential player in the set-up and there's no doubt he'll be missed for the game against Australia. But where there is an injury, there's an opportunity for someone else.
"We've had five or six front line players missing throughout the series, so I've no doubt we'll adapt and work that little bit harder this week.
"I'm sure the players will respond to this by going up a level and peak for this game."
Vunipola's absence will also be felt by Premiership leaders Saracens, who resume their defence of the European Champions Cup next month.
Agence France-Presse
