Freddie Steward and Jack van Poortvliet will return for England on Saturday, with Steve Borthwick making four changes against South Africa.
England were unchanged for their narrow defeats against New Zealand and Australia, but the Leicester pair, who were not included in the squad for either of those matches, come straight in to replace George Furbank and Ben Spencer.
Ollie Sleightholme scored his first international tries in the defeat to Australia and is rewarded with a maiden Test start in place of Immanuel Feyi-Waboso, while Sam Underhill comes in for Tom Curry, with both players missing due to head injuries.
England have lost each of their last four Test matches, their longest such run since losing five straight games in 2018.
"We're excited to challenge ourselves against the world's top-ranked team and back-to-back Rugby World Cup champions," Borthwick said.
"Test matches against South Africa are always thrilling contests, and I'm sure Saturday will be no exception."
Meanwhile, South Africa have made 12 changes to their starting XV from their 32-15 win over Scotland on Sunday.
Captain Siya Kolisi and Pieter-Steph du Toit return in the back row, while Cheslin Kobe is also named in the side.
The world champions have got a more balanced look to their bench this time around though, with coach Rassie Erasmus opting not to name seven forwards among the replacements this time around.
England squad in full:
Freddie Steward, Tommy Freeman, Ollie Lawrence, Henry Slade, Ollie Sleightholme, Marcus Smith, Jack van Poortvliet, Ellis Genge, Jamie George (captain), Will Stuart, Maro Itoje, George Martin, Chandler Cunningham-South, Sam Underhill, Ben Earl.
Replacements: Luke Cowan-Dickie, Fin Baxter, Dan Cole, Nick Isiekwe, Alex Dombrandt, Harry Randall, George Ford, Tom Roebuck.
South Africa squad in full:
Alphelele Fassi, Cheslin Kolbe, Jesse Kriel, Damian De Allende, Kurt-Lee Arendse, Maine Libbok, Grant Williams, Ox Nche, Bongi Mbonambi, Wilco Loux, Eben Etzebeth, RG Snyman, Siya Kolisi (captain), Pieter-Steph Du Toit, Jasper Wiese.
Replacements: Malcolm Marx, Gerhard Steenekamp, Vincent Koch, Elrigh Louw, Kwagga Smith, Cobus Reinach, Handre Pollard, Lukhanyo Am.
'World-class' Scotland will provide Wallabies' sternest test – Skelton
Australia will face their sternest test to date when they continue their autumn tour against a "world-class" Scotland team at Murrayfield on Sunday.
That is the view of forward Will Skelton, who believes the Wallabies' victories in England and Wales have brought a new energy and confidence to their camp.
Having crashed out in the pool stage at last year's World Cup in France before finishing last in the Rugby Championship, Australia have looked a team reborn in recent weeks.
A first victory at Twickenham since 2015 and a 52-20 rout of Wales – their biggest-ever away win in matches between the teams – have made it an excellent tour to date for Joe Schmidt's side.
But La Rochelle lock Skelton feels their toughest assignment is to come this week, saying: "We've won two games, we're very aware of that.
"The Test against Scotland is going to be the hardest one yet. We're excited about this weekend and we're looking forward to ripping into it.
"Physically they're up there with the top five in the world. I think set-piece wise they're really strong.
"You've got a guy like Finn Russell who's a maestro at the back there. I think it's going be a close one and we'll be up for it.
"There's some class players in the Scottish team and, when they're at it they're world-class, so we're going to have to be on top of our game."
Wales must 'show courage and front up' against South Africa, says Gatland
Warren Gatland has urged Wales to "show real courage and front up" in their final Autumn Nations clash against South Africa.
Gatland's side bring the curtain down on a disappointing year when they welcome the reigning world champions to the Principality Stadium on Saturday.
Wales have lost an unprecedented 11 straight Tests, and could go an entire calendar year without tasting success for the first time since 1937.
Gatland has made four changes from last weekend's 52-20 defeat to Australia, with Sam Costelow, Rio Dyer, Christ Tshiunza and Taine Plumtree all coming into the starting XV.
Gareth Anscombe, Aaron Wainwright and Cameron Winnett drop out of the squad, while Adam Beard misses out through injury.
And Gatland wants his players to demonstrate fighting spirit against the Springboks.
"Last week's result hurts, and we are just as disappointed by it as the fans," he told reporters during his pre-match press conference.
"Our focus now is on training and preparing well for our final game of this Autumn Nations Series.
"There were good elements that we can definitely build on going into Saturday, but we have to improve our accuracy.
"We know what a quality side South Africa are and the physicality they bring. This week, we need to show real courage and front up against the world champions."
'Playing for England is the Mecca' according to Itoje amid global breakaway talk
Maro Itoje has reaffirmed his commitment to England amid talks of a proposed global breakaway league.
Steve Borthwick’s side are looking to end their five-match losing run when they face Japan in their final match of the autumn series on Sunday.
But there is fear that Borthwick could lose many of his players to the new league that reportedly are offering 40 £1m-a-season contracts for marquee players and more periods of rests for the players.
The Rugby Football Union (RFU) only select players for the national team from English clubs, meaning any player joining the breakaway league would jeopardise their Test career.
But Itoje has insisted that playing for England is the pinnacle for him and his teammates.
"I don't really know any of the details of it as yet, but wearing this rose is extremely important to me and my teammates," said Itoje.
"Playing for England is the Mecca."
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