Hooker Tom Youngs will make his England debut against Fiji on Saturday, while boss Stuart Lancaster has also named two uncapped players on the bench.
There are five changes in the XV, with captain Chris Robshaw back on the flank and Charlie Sharples, Ugo Monye and Brad Barritt coming into the back line.
Uncapped Wasps back row Joe Launchbury and Saracens prop Mako Vunipola are both among the replacements.
Youngs is the brother of scrum-half Ben, who is on the bench.
It is one of the most inexperienced England teams of the professional era, with the starting XV averaging just over 14 caps per man while the replacements have only eight-and-a-half caps per man.
"This is the start of a huge four-week journey for us that will test us in every way," Lancaster said. "It is about putting a marker down at the start of this series.
"There is a lot of consistency from the South Africa tour [which England lost 2-0 in the summer], particularly the team that played in the last Test, which is based on form in the Premiership."
Tom Youngs, who only switched to hooker from centre three years ago, gets his chance in the number two shirt because of first-choice hooker Dylan Hartley's knee injury.
The 25-year-old has only started 10 games for Leicester and his throwing into the line-out has been called into question on occasion, but Lancaster is confident the hooker is ready for the Test stage.
"There are not many centres who transfer from hooker so mental resilience and toughness is one of his strengths," Lancaster explained.
"So too are his physicality, his handling, his defence and his set piece. He has areas to work on but the scrum power he brings is phenomenal.
"People make a lot of his throwing but he has done it consistently in big games.
"He deserves his chance, as do Joe Launchbury and Mako Vunipola, who we are pleased to be able to include in the squad."
Young's younger brother Ben has only recently returned to action after injury and is edged out for the scrum-half berth by in-form Harlequins number nine Danny Care.
Gloucester's Sharples replaces the suspended Chris Ashton on the right wing, Harlequins' Monye comes in for the injured Ben Foden on the left and Saracens centre Barritt replaces another injury victim, Jonathan Joseph, in the centres.
Harlequins flanker Robshaw missed the final Test of the summer against South Africa because of injury and the captain replaces James Haskell in the back row alongside Tom Johnson and Thomas Waldrom.
Care and Toby Flood - the most experienced player in the team with 50 caps - form the half-back partnership while Saracens' Alex Goode starts at full-back.
Northampton flanker Tom Wood returns to the England fold after 14 injury-plagued months with a place on the bench.
England face Fiji, Australia, South Africa and New Zealand at Twickenham over consecutive weekends.
England team to face Fiji: Alex Goode (Saracens); Charlie Sharples (Gloucester), Manu Tuilagi (Leicester), Brad Barritt (Saracens), Ugo Monye (Harlequins); Toby Flood (Leicester), Danny Care (Harlequins); Joe Marler (Harlequins), Tom Youngs (Leicester), Dan Cole (Leicester), Tom Palmer (Wasps), Geoff Parling (Leicester), Tom Johnson (Exeter), Chris Robshaw (Harlequins, capt), Thomas Waldrom (Leicester).
Replacements: David Paice (London Irish), David Wilson (Bath), Mako Vunipola (Saracens), Joe Launchbury (Wasps), Tom Wood (Northampton), Ben Youngs (Leicester), Owen Farrell (Saracens), Mike Brown (Harlequins)