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Full-back George Furbank has been ruled out of England's Nations Championship opener against South Africa in Johannesburg on Saturday with appendicitis.
Furbank, 29, had been preparing for his first England game in nearly two years before falling ill on Friday evening.
Marcus Smith has replaced him at 15, with Henry Slade stepping up to the bench.
Steve Borthwick's side face the world champion Springboks at 16:40 BST at the iconic Ellis park in Johannesburg.
Furbank's inclusion had been one of the main talking points from Thursday's team announcement.
"George Furbank has had so many little setbacks that would really test anybody's character and resolve and he has come through it all," head coach Steve Borthwick said on Thursday.
With that in mind, it is another desperately unlucky setback for the 29-year-old, who has suffered arm, calf, knee and concussion injuries since his most recent England appearance in November 2024.
"It feels like a significant blow to England's attacking prospects, as well as the leadership a Prem-winning captain brings to the backfield," said former England fly-half Paul Grayson.
Furbank impressed at full-back throughout the course of 2024, but was hit by a succession of injuries since his most recent appearance against Japan in November of that year.
However, he returned to hit top form at the back end of the latest Prem season, leading Northampton to the league title before a summer switch to Harlequins.
The Springboks have been forced into their own late changes, with Eben Etzebeth and Siya Kolisi, both double Rugby World Cup winners, forced out of the starting line-up with injuries picked up after South Africa's team announcement on Monday.
Pieter-Steph du Toit takes on the captaincy from Kolisi and switches into the second row, with Paul de Villiers and Cameron Hanekom coming into the back row, either side of number eight Jasper Wiese.
The Stormers flanker Ben-Jason Dixon comes onto the bench.
England: Smith; Feyi-Waboso, Freeman, Atkinson, Murley: F Smith, Van Poortvliet; Genge, George, Heyes, Coles, Martin, Chessum, Curry, Earl
Replacements: Cowan-Dickie, Obano, Opoku-Fordjour, Ewels, Pepper, Pollock, Mitchell, Slade
South Africa: Willemse; Kolbe, Kriel, De Allende, Arendse; Libbok, Williams; Nche, Marx, T du Toit, P-S du Toit (c), Nortje, De Villiers, Hanekom, Wiese
Replacements: Wessels, Steenekamp, Porthen, Van Staden, Dixon, Reinach, Esterhuizen, Moodie
English (US) ·