Uncapped Sale scrum-half Raffi Quirke and Northampton back Tommy Freeman, both 20, have been named in the England squad for the autumn internationals.
Two more uncapped players in Gloucester centre Mark Atkinson and Leicester hooker Nic Dolly make the 34-man squad.
However, there is no place for 50-cap stars Mako and Billy Vunipola, George Ford and Jamie George.
Harlequins fly-half Marcus Smith is included and Owen Farrell has been confirmed as captain.
England face Tonga on 6 November, Australia on 13 November and world champions South Africa on 20 November.
“This is a young but very good, talented squad who have all earned their places,” said head coach Eddie Jones.
“It is one of the most competitive squads I have ever picked.”
After being left out of last month’s England training squad, Ford has been in excellent form for the unbeaten Leicester Tigers, while the Vunipolas and George were at their best in Saracens’ 70-point dismantling of Bath on Sunday, with Sarries boss Mark McCall saying afterwards he would be “amazed” if his experienced trio were again overlooked.
But while Jones insists the “door is not closed” for any player, the omission of such high-calibre individuals shows the England boss is determined to revamp his squad, especially given the poor Six Nations and the oft-stated desire to build towards the 2023 Rugby World Cup.
In George’s absence, hooker Dolly is rewarded for his strong early-season performances with the Tigers, while Ford’s omission paves the way for Quins star Smith to grab the number 10 shirt.
Number eights Callum Chick, Sam Simmonds and Alex Dombrandt can all profit from Billy Vunipola missing out, although it is understood Jones still views Tom Curry as an option at the back of the scrum.
Another surprising absentee is scrum-half Dan Robson, with rookie nines Harry Randall – who won his first caps in the summer – and Quirke both preferred.
England squad for autumn Tests:
Forwards: Jamie Blamire (Newcastle), Callum Chick (Newcastle), Luke Cowan-Dickie (Exeter), Tom Curry (Sale), Trevor Davison (Newcastle), Nic Dolly (Leicester), Alex Dombrandt (Harlequins), Charlie Ewels (Bath), Ellis Genge (Leicester), Jonny Hill (Exeter), Maro Itoje (Saracens), Courtney Lawes (Northampton), Lewis Ludlam (Northampton), Joe Marler (Harlequins), George Martin (Leicester), Sam Simmonds (Exeter), Kyle Sinckler (Bristol), Will Stuart (Bath), Sam Underhill (Bath)
Backs: Mark Atkinson (Gloucester), Owen Farrell (Saracens), Tommy Freeman (Northampton), George Furbank (Northampton), Max Malins (Saracens), Jonny May (Gloucester), Raffi Quirke (Sale), Adam Radwan (Newcastle), Harry Randall (Bristol), Henry Slade (Exeter), Marcus Smith (Harlequins), Freddie Steward (Leicester), Manu Tuilagi (Sale), Anthony Watson (Bath), Ben Youngs (Leicester)
Quirke scored twice against Harlequins on Friday night, with his boss Alex Sanderson telling BBC 5 live afterwards the young playmaker could go on to be a legend of English rugby.
“If he stays fit he’s probably going to be one of the country’s greats,” Sanderson said. “I’ve spoken to Eddie and he is one of the smartest coaches around. I trust he will have not just England’s best interests [at heart] but Raffi’s as well.”
Luke Cowan-Dickie, Maro Itoje and Anthony Watson have all been named despite injury scares on the weekend, while Joe Launchbury and Elliot Daly are long-term injury absentees.
With Daly out, Max Malins, Freeman and Leicester’s Freddie Stewart, who made his debut in July, are contenders for the full-back position, with Steward expected to be given an extended run in the 15 shirt.
In total there are eight players who made their debuts in the summer Tests against the USA and Canada, with Newcastle front-row pair Jamie Blamire and Trevor Davison, as well as two more Falcons in Chick and the electric Adam Radwan, joining Steward, Dombrandt, Randall and Smith in the squad.