Vunipola, whose brother Billy is not named in the 23, replaces Harlequins’ Joe Marler at loosehead with Leicester Tigers hooker Tom Youngs also coming into the front row in place of Dylan Hartley.
With Owen Farrell sidelined by a calf injury Toby Flood takes over at fly-half and will be partnered by Danny Care at No9, who replaces Ben Youngs.
James Haskell returns at blindside flanker in place of Courtney Lawes while Tom Croft is among the replacements, returning to the squad for the first time since breaking a bone in his neck 12 months ago.
Fit-again Freddie Burns is also back on the bench and after coming from behind to beat France, Lancaster admits he will not hesitate to call on his replacements again.
“We were very happy with the way we finished the France game,” he said.
“The impact the replacements made shows that we have competition for places across the board and we have had to make some tight calls.
“Italy will be highly motivated for this game and we will have to perform for the full 80 minutes. I am sure those starting will seize their chance and the bench will also have a significant part to play as the game goes on.
“The support at Twickenham for the Scotland and France games was superb and I am sure the atmosphere will be fantastic again for our final home match of the Championship.”
England team to face Italy: 15. Alex Goode (Saracens, 9 caps); 14. Chris Ashton (Saracens, 32 caps), 13. Manusamoa Tuilagi (Leicester Tigers, 19 caps), 12. Brad Barritt (Saracens, 14 caps), 11. Mike Brown (Harlequins, 14 caps); 10. Toby Flood (Leicester Tigers, 55 caps), 9. Danny Care (Harlequins, 39 caps); 1. Mako Vunipola (Saracens, 7 caps), 2. Tom Youngs (Leicester Tigers, 7 caps), 3. Dan Cole (Leicester Tigers, 38 caps), 4. Joe Launchbury (London Wasps, 7 caps), 5. Geoff Parling (Leicester Tigers, 15 caps), 6. James Haskell (London Wasps, 48 caps), 7. Chris Robshaw (Harlequins, capt, 15 caps), 8. Tom Wood (Northampton Saints, 16 caps)
Replacements: 16. Dylan Hartley (Northampton Saints, 45 caps), 17. David Wilson (Bath Rugby, 24 caps), 18. Joe Marler (Harlequins, 8 caps), 19. Courtney Lawes (Northampton Saints, 18 caps), 20. Tom Croft (Leicester Tigers, 36 caps), 21. Ben Youngs (Leicester Tigers, 31 caps), 22. Freddie Burns (Gloucester Rugby, 1 cap), 23. Billy Twelvetrees (Gloucester Rugby, 2 caps)
MORE: The latest football news