Bath winger Anthony Watson will make his first start for England in place of the injured Semesa Rokoduguni against South Africa.
The 20 year-old has been handed a chance to build on his cameo appearance from the bench in last weekend's 24-21 defeat to New Zealand.
A prolific graduate of the England age-group system who was part of the 2013 Junior World Championship-winning side, Watson can also draw confidence from the tour to New Zealand.
Watson's promotion means Harlequins flyer Marland Yarde, who has scored four tries in five international appearances thus far, comes onto the bench.
Elsewhere in the starting XV, Dylan Hartley and Courtney Lawes (both Northampton Saints) successfully completed the graduated return to play protocol. They are named to start and will take part in Thursday's training session, while scrum-half Danny Care will become the squad's second half-centurion after Hartley.
England Head Coach Stuart Lancaster said: "Anthony has been pushing hard for a while and has been in impressive form for Bath and in training with us.
"It was great that he got on against New Zealand and we feel he is ready to start. Equally, it's good to have Marland back in the matchday 23.
"Congratulations to Danny Care who will be winning his 50th cap. It'll be a special moment for him and I am sure he will rise to the occasion."
England are on a run of four consecutive defeats and have not overturned the Springboks in 11 matches stretching back to 2006. Still, Lancaster highlighted the determination and diligence that has characterised this week's preparation.
"I know the players are looking forward to the challenge," he added. "South Africa have quality and experience across the park and it will be a big test for us."
England: 15 Mike Brown, 14 Anthony Watson, 13 Brad Barritt, 12 Kyle Eastmond, 11 Jonny May, 10 Owen Farrell, 9 Danny Care, 8 Billy Vunipola, 7 Chris Robshaw (c), 6 Tom Wood, 5 Courtney Lawes, 4 Dave Attwood, 3 David Wilson, 2 Dylan Hartley, 1 Joe Marler
Replacements: 16 Rob Webber, 17 Matt Mullan, 18 Kieran Brookes, 19 George Kruis, 20 Ben Morgan, 21 Ben Youngs, 22 George Ford, 23 Marland Yarde
Date: Saturday, November 15
Kickoff: 14:30 local (GMT)
Venue: Twickenham, London
Referee: Steve Walsh (Australia)
Assistant Referees: Jérôme Garcès (France),Nick Briant (New Zealand)
TMO: Eric Gauzins (France)
