Billy Vunipola, seen here in action against the Springboks in June, has sustained a broken arm.
"Nick Isiekwe, Billy Vunipola and Mako Vunipola are set for a spell on the sidelines", Saracens confirmed in a statement. "Billy has an arm injury but it's not the same arm he injured before".
The 25-year-old will undergo surgery on Tuesday and is expected to be out for around 12 weeks. According to Saracens his "progress will be monitored". Nick Isiekwe sprained his ankle and is being assessed to determine the full extent of the problem.
Only last month, Billy Vunipola struck a disarmingly honest chord when admitting he had previously tried to "be a hero" and play through the pain of injury.More news: Sights and sounds of last season's Wisconsin-Michigan game
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The injury comes not only as a huge blow to Saracens, but to England as well.
Eddie Jones is due to name his England squad for the internationals against South Africa, New Zealand, Japan and Australia on Thursday. Ben Morgan, unused since the 2015 Rugby World Cup, could become an option again.
Both brothers, who have been named in England's training squad for the forthcoming global series, retreated to the bench, with Mako pictured with his leg in a protective brace and Billy with his arm packed in ice.
He missed the 2017 British and Irish Lions tour after shoulder surgery before then suffering a serious knee injury and two consecutive right-arm fractures.