Danny Cipriani has been left out of England's 36-man squad for the autumn internationals against South Africa, New Zealand, Japan and Australia next month.
Cipriani was not included in head coach Eddie Jones' training squad that met in Bristol in September, but the fly-half was then named as the Premiership's Player of the Month for his impressive performances for Gloucester.
Exeter Chiefs props Ben Moon, who is one of eight uncapped players to be selected, and Alec Hepburn have been called up to replace Mako Vunipola, who was injured alongside brother Billy in Saracens' Champions Cup win away to Glasgow on Sunday.
"We can only control what we can control and injuries have happened," Jones told the RFU. "It gives an opportunity for some good new players to play some important Tests for England while players who have been in the squad before, will have to take on more responsibility."
Chris Ashton has also been named in the squad, despite not playing a minute of action for Sale this season. Ashton's seven-week ban for a dangerous tackle in pre-season ended this week and the winger is set to start Sale's Challenge Cup fixture against Connacht this weekend.
Owen Farrell and Dylan Hartley have been named as co-captains for the four Tests, as England step up their preparations for next year's Rugby World Cup in Japan, while Joe Cokanasiga, Nathan Earle, Ted Hill, Zach Mercer, Michael Rhodes, Nick Schonert and Elliott Stooke could all make their England debuts.
Dave Attwood and Don Armand miss out, as well as James Haskell and Dan Cole, while Ellis Genge, Jonathan Joseph, Dan Robson and Anthony Watson are other notable players who are unavailable for selection due to injury.
Forwards (20): Tom Curry (Sale Sharks), Charlie Ewels (Bath Rugby), Jamie George (Saracens), Dylan Hartley (Northampton Saints), Alec Hepburn (Exeter Chiefs), Ted Hill (Worcester Warriors), Maro Itoje (Saracens), George Kruis (Saracens), Courtney Lawes (Northampton Saints), Zach Mercer (Bath Rugby), Ben Moon (Exeter Chiefs), Ben Morgan (Gloucester Rugby), Michael Rhodes (Saracens), Nick Schonert (Worcester Warriors), Brad Shields (Wasps), Kyle Sinckler (Harlequins), Elliott Stooke (Bath Rugby), Sam Underhill (Bath Rugby), Harry Williams (Exeter Chiefs), Mark Wilson (Newcastle Falcons)
Backs (16): Chris Ashton (Sale Sharks), Mike Brown (Harlequins), Danny Care (Harlequins), Joe Cokanasiga (Bath Rugby), Elliot Daly (Wasps), Nathan Earle (Harlequins), Owen Farrell (Saracens), George Ford (Leicester Tigers), Alex Lozowski (Saracens), Jonny May (Leicester Tigers), Jack Nowell (Exeter Chiefs), Henry Slade (Exeter Chiefs), Ben Te'o (Worcester Warriors), Manu Tuilagi (Leicester Tigers), Richard Wigglesworth (Saracens), Ben Youngs (Leicester Tigers)