England will give debuts to centre Guy Porter and wing Tommy Freeman for the second Test against Australia in Brisbane on Saturday.
Sam Underhill comes in at openside with Tom Curry ruled out with concussion.
"We have decided to make changes in our backline, they were tough calls but we feel they will strengthen the team," said head coach Eddie Jones.
"There are opportunities to attack against Australia which we can take."
Freeman, 21, played for England in the defeat by the Barbarians in June, in a non-cap international.
He replaces Joe Cokanasiga on the left wing, while Porter comes in for Joe Marchant at outside centre and 21-year-old Van Poortvliet starts instead of Danny Care.
Wing Jonny May is not included as he continues his recovery from Covid, while Jones has kept faith with the combination of Marcus Smith at fly-half and Owen Farrell at inside centre.
Back row Jack Wills also comes onto the bench, alongside last weekend's try-scorer Henry Arundell.
"We have had solid preparation this week and looking forward to an important game in Brisbane," added Jones.
"This game is the perfect practice for the World Cup and our focus is putting on our best performance."
Australia have made a host of enforced changes as they look to clinch the series.
But in a major boost, experienced prop Taniela Tupou is available and replaces the injured Allan Ala'alatoa.
Matt Philip starts at lock with Darcy Swain suspended and Hunter Paisami comes into the midfield, with Tom Wright on the wing and Jordan Petaia starting at full-back in the absence of the injured Tom Banks.
Analysis - Jones rolling the dice
Chris Jones, BBC rugby union correspondent
Ahead of the first Test in Perth, Eddie Jones was in buoyant mood, declaring how he had selected his strongest team on paper in ages.
However that side failed to fire and crashed to defeat after a final-quarter Wallaby barrage, leading Jones to ring the changes in the backline - which jars with his oft-stated desire for cohesion.
The hope will be the humid Brisbane conditions and quick surface will be tailor-made for rookies like Tommy Freeman and Jack van Poortvliet, but it feels like Jones is rolling the dice for a game he - and England - can ill-afford to lose.
Teams
Australia: Petaia; Wright, Paisami, Kerevi, Koroibete; Lolesio, White; Bell, Porecki, Tupou, Philip, Neville, Leota, Hooper (captain), Valetini
Replacements: Fainga'a, Sio, Slipper, Frost, Samu, Gordon, O'Connor, Perese
England: Steward; Nowell, Porter, Farrell, Freeman; Smith, Van Poortvliet; Genge, George, Stuart, Itoje, Hill, Lawes (captain), Underhill, B Vunipola
Replacements: Cowan-Dickie, M Vunipola, Heyes, Chessum, Ludlam, Willis, Care, Arundell