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.