Exeter's double-winning lock Jonny Hill will make his England debut in Saturday's Six Nations match against Italy in Rome.
Hill starred as the Chiefs won a domestic and European double this month and joins Maro Itoje in the second row.
Scrum-half Ben Youngs wins his 100th cap, becoming the second Englishman to do so after Jason Leonard.
England could seal the Six Nations title with a win if the result of France v Ireland goes their way.
Hooker Tom Dunn and backs Ollie Lawrence and Ollie Thorley are set for their debuts from the bench.
As well as Youngs, starting hooker Jamie George reaches a milestone at the Stadio Olimpico as he wins his 50th cap.
With fly-half George Ford and centre Manu Tuilagi unavailable, captain Owen Farrell will start at 10 and is joined by Henry Slade and Jonathan Joseph in the midfield.
Northampton's George Furbank starts at full-back in the absence of the injured Elliot Daly.
Even with a bonus-point victory, England would not be confirmed Six Nations champions until after France play Ireland.
England team to face Italy
Furbank; Watson, Joseph, Slade, May; Farrell, Youngs; M Vunipola, George, Sinckler, Itoje, Hill, Curry, Underhill, B Vunipola.
Replacements: Dunn, Genge, Stuart, Ewels, Earl, Robson, Lawrence, Thorley.
New faces come in as injury list grows
The presence of four uncapped players in the matchday 23 comes as head coach Eddie Jones battles with a growing list of injured players.
Wasps scrum-half Dan Robson is set to win his third cap off the bench after Willi Heinz was ruled out on Wednesday with a leg injury.
Exeter hooker Luke Cowan-Dickie, club-mate Jack Nowell, Joe Marler and Courtney Lawes are also injured.
Wasps fly-half Jacob Umaga has been overlooked, leaving no obvious 10 on the bench but Jones did suggest earlier in the week he had been trying Furbank in that position.
Forwards coach Matt Proudfoot said in-form Wasps flanker Jack Willis was "ready for Test rugby" but the 23-year-old has not made it into the squad, with Bristol's Ben Earl on the bench instead.
England's Six Nations resumes
England will play their first match since lockdown following a seven-month interruption to the Six Nations caused by the coronavirus pandemic and the cancellation of last week's scheduled Barbarians Test. Here's how they have fared so far: