Saints' three England stars will start on the bench in Saturday's game against Samoa at Twickenham (kick-off 3pm).
Dylan Hartley, Courtney Lawes and Piers Francis are all among the replacements.
But one Saints player will start, with Ahsee Tuala lining up at full-back for Samoa.
Boss Eddie Jones has made nine changes to the England first 15 that beat Australia 30-6 last weekend.
George Ford and Chris Robshaw are named as co-captains, a role they played in England’s Old Mutual Wealth Cup match against the Barbarians in May.
Robshaw moves to openside with Maro Itoje starting at blindside.
Sam Simmonds will make his first start for England at No.8 in the absence of Nathan Hughes.
Jamie George replaces Hartley at hooker, while Ellis Genge comes in for Mako Vunipola.
Charlie Ewels will start alongside last weekend’s man of the match Joe Launchbury in the second row.
Alex Lozowski and Henry Slade are the centre combination with Mike Brown returning to the starting 15 after missing the Australia Test due to injury.
Danny Care will start his first Test of the series with Ben Youngs named as a replacement.
England head coach Jones said: “This is an exciting squad to play against Samoa and we are expecting them to be immensely physical and committed this weekend.
“We want to follow up last week’s performance against Australia and play better again this week. Our intent in every game and every training session is to be better.
“This week it is an opportunity for some squad members who haven’t been playing to put their best foot forward.
"We will have to play smart and will need to find ways to win the contest against Samoa.
“The crowd last week were outstanding and we want to put on a good performance again for them this weekend.”
England team to play Samoa
15 Mike Brown (Harlequins 63 caps)
14 Jonny May (Leicester Tigers 28 caps)
13 Henry Slade (Exeter Chiefs 9 caps)
12 Alex Lozowski (Saracens 3 caps)
11 Elliot Daly (Wasps 15 caps)
10 George Ford (Leicester Tigers 39 caps) co-captain
9 Danny Care (Harlequins 75 caps)
1 Ellis Genge (Leicester Tigers 4 caps)
2 Jamie George (Saracens 19 caps)
3 Dan Cole (Leicester Tigers 76 caps)
4 Joe Launchbury (Wasps 46 caps)
5 Charlie Ewels (Bath Rugby 5 caps)
6 Maro Itoje (Saracens 13 caps)
7 Chris Robshaw (Harlequins 58 caps) co-captain
8 Sam Simmonds (Exeter Chiefs 2 caps)
16 Dylan Hartley (Saints 88 caps)
17 Joe Marler (Harlequins 52 caps)
18 Harry Williams (Exeter Chiefs 4 caps)
19 Nick Isiekwe (Saracens 1 cap)
20 Courtney Lawes (Saints 60 caps)
21 Ben Youngs (Leicester Tigers 72 caps)
22 Piers Francis (Saints 2 caps)
23 Semesa Rokoduguni (Bath Rugby 3 caps)