Bath fly-half Orlando Bailey, Leicester forward Ollie Chessum, Northampton full-back Tommy Freeman and Wasps back-rower Alfie Barbeary are the four other rookies in the 36-man squad, who will meet in Brighton on Monday for a five-day training camp.
Bailey has got the nod over experienced fly-half George Ford, who has been in fine form for Leicester this season.
The 28-year-old had been hoping for a recall this month, but he has been omitted as Eddie Jones looks to build his team around Harlequins fly-half Marcus Smith.
Fellow experienced duo Billy and Mako Vunipola and Elliot Daly have once again been overlooked by Jones, but the trio’s Saracens team-mate Jamie George has kept his place after impressing in the autumn, when he was called up to replace the injured Luke Cowan-Dickie.
Owen Farrell has been named captain and he will hope to return to action for Saracens this weekend against London Irish after being out since November with an ankle problem.
There had originally been fears that Farrell could miss the start of the Six Nations, but he is back involved and will hope to play in England’s opener against Scotland on February 5.
After the RFU struck a deal with the Premiership, Jones can tweak his squad for each match during the Six Nations – with the likes of Bath flanker Sam Underhill and Leicester centre Manu Tuilagi hoping to play some part in the tournament after being left out today.
The flexibility also helps Jones when selecting squads for the trips to France and Italy, with unvaccinated players unlikely to be able to play due to strict rules there.
England met the 85 per cent vaccination target for the autumn internationals, but the centre Henry Slade is among those to have previously expressed hesitancy.