Head coach Steve Borthwick has stood Itoje down from the opening phase of the Nations Championship after second rows Alex Coles and George Martin came through the weekend's action without any fitness issues.
It follows a year in which Itoje led the British and Irish Lions to a series victory against Australia, played in the pre-Christmas and Six Nations campaigns and mourned the death of his mother.
It would also be in recognition of the 31-year-old having completed more Test minutes than any other player in the game over the last decade.
Borthwick has placed George in charge, with the veteran Lions hooker seen as an ideal alternative given he skippered England throughout 2024 before being replaced by Itoje.
South African-born centre Benhard Janse van Rensburg has been included in Borthwick's 36-man squad having made his England debut in the uncapped game against France on Friday night.
The 29-year-old Bristol centre does not qualify on residency grounds until July 8, meaning he will miss the tour opener against the Springboks in Johannesburg on Saturday week and must wait until Fiji on July 11 for his first Test appearance.
Noah Caluori is rewarded for his breakthrough season at Saracens in which he finished as the Prem's leading try-scorer by also being included among five five uncapped players.
Number eight Greg Fisilau and props George Kloska and Vilikesa Sela complete the quintet of Test rookies on a 25,000-mile trip that spans three continents.Â
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