Luther Burrell and Jonathan Joseph will form a new England midfield partnership after coach Stuart Lancaster announced his team Wednesday for Friday's Six Nations opener against Wales in Cardiff.
Meanwhile the experienced pair of fly-half Danny Cipriani and back-row forward Nick Easter found themselves on the bench as they were both recalled to Test duty.
Prop Dan Cole returned at tighthead having recovered from a foot problem for his first Test appearance in almost a year.
England had already seen powerhouse centre Manu Tuilagi sidelined with a groin problem ahead of the Millennium Stadium clash while fellow midfielders Brad Barritt (knee) and Kyle Eastmond (shoulder) also failed to make it into contention for the Wales match.
But Burrell, who suffered a recent concussion playing for Northampton against Racing Metro, has been passed fit.
Joseph has made an excellent start to the Premiership season with Bath and Friday's match will see him win his seventh cap but first in the Six Nations.
- 'Form centres' -
"Jonathan has been one of the form centres in the country. He and Luther have trained well together and this is a big opportunity for both of them," said Lancaster in a Rugby Football Union statement.
Talented fly-half Cipriani featured in two of England's three Tests in New Zealand in June, ending a six-year international exile, but the 27-year-old was omitted from the November campaign.
However, he has now edged his way past Stephen Myler and provides cover for first-choice No.10 George Ford.
Easter has not played for England since Lancaster took charge following the side's 2011 World Cup exit where the No.8 won the last of his 47 caps, but has been recalled after impressing for Harlequins.
England's injury crisis can be gauged from the fact Wednesday's team features only nine survivors from the side that started the 26-17 victory over Australia at Twickenham last time out in November, and just five from the XV thrashed 30-3 by Wales in Cardiff two years ago.
Joseph and Burrell were the only changes to the backline that beat Australia, with Ben Youngs and Ford continuing their half-back partnership.
But up front, Ben Morgan, who scored two tries against the Wallabies, has been ruled out of the entire Six Nations and his place at No.8 has gone to Billy Vunipola.
James Haskell also slotted into a back-row featuring England captain Chris Robshaw after Tom Wood was sidelined with an ankle problem.
England, without first-choice locks Joe Launchbury and Courtney Lawes, have paired Dave Attwood alongside George Kruis, who has not played for three weeks after being banned for a dangerous tackle.
Cole was given a front-row berth after David Wilson was ruled out with a neck injury.
World Cup hosts England have gone for as much experience as they can muster against Wales, a team they will meet in the pool stages of the global showpiece later this year at Twickenham.
"Billy Vunipola has been playing well for Saracens and it's good to be able to give George Kruis his first international start after his impressive run off the bench in November," said Lancaster.
"Dan Cole and James Haskell bring a lot of experience, as do the bench, and their contribution will be crucial on Friday night."
Dylan Hartley saw off competition for his place at hooker from Tom Youngs despite a poor disciplinary record that has led to 50 weeks' worth of suspensions for the New Zealand-born forward.
Wales coach Warren Gatland named his side on Monday, 48 hours ahead of schedule.
The New Zealander made just two changes to the team that beat South Africa 12-6 in November, with the British and Irish Lions pair of wing George North and hooker Richard Hibbard recalled.
England (15-1)
Mike Brown; Anthony Watson, Jonathan Joseph, Luther Burrell, Jonny May; George Ford, Ben Youngs; Billy Vunipola, Chris Robshaw (capt), James Haskell; George Kruis, Dave Attwood; Dan Cole, Dylan Hartley, Joe Marler
Replacements: Tom Youngs, Mako Vunipola, Kieran Brookes, Tom Croft, Nick Easter, Richard Wigglesworth, Danny Cipriani, Billy Twelvetrees
Source: AFP