Sam Underhill has withdrawn from England's Six Nations squad with a hip injury and been replaced by Wasps' Jack Willis.
Underhill would have been likely to have started the opening fixture against Scotland at Twickenham on February 6 but he could now miss the entire tournament.
News of his injury comes the day after prop Joe Marler pulled out of the 28-man squad to be with his family during the coronavirus pandemic and Joe Launchbury learned he would sit out the first three rounds with a broken leg.
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Willis has been promoted from England's 12-strong 'shadow squad' and will compete with Ben Earl and Mark Wilson for the vacancy created by Underhill's absence.
Lewis Ludlam fills Willis' slot in the second group of players, who are subject to the same Covid-19 testing procedures as the 28 in the event that injuries mean new personnel must be brought in.
Adding depth at loosehead prop and lock to the shadow squad in the wake of the withdrawal of Marler and Launchbury are Alex Hepburn and David Ribbans.
Eddie Jones' squad will meet at St. George's Park on Wednesday ahead of their first game of the tournament against Scotland at Twickenham on February 6.
England's 28-man Six Nations squad
Backs (12): Elliot Daly, Anthony Watson, Max Malins, Jonny May, Paolo Odogwu, Henry Slade, Ollie Lawrence, Owen Farrell, George Ford, Ben Youngs, Dan Robson, Harry Randall.
Forwards (16): Beno Obano, Ellis Genge, Tom West, Will Stuart, Harry Williams, Jamie George, Luke Cowan-Dickie, Maro Itoje, Charlie Ewels, Jonny Hill, Courtney Lawes, Tom Curry, Jack Willis, Mark Wilson, Billy Vunipola, Ben Earl.
Shadow Squad (12): Charlie Atkinson, Ali Crossdale, Tom Dunn, George Furbank, Joe Heyes, Jonathan Joseph, Joe Marchant, George Martin, Alex Mitchell, Jacob Umaga, Alex Hepburn, David Ribbans.
England's 2021 Six Nations fixtures
- Scotland - Twickenham - Saturday, February 6 - 4.45pm (GMT)
- Italy - Twickenham - Saturday, February 13 - 2.15pm (GMT)
- Wales - Principality Stadium - Saturday, February 27 - 4.45pm (GMT)
- France - Twickenham - Saturday, March 13 - 4.45pm (GMT)
- Ireland - Aviva Stadium - Saturday, March 20 - 4.45pm (GMT)