Key forward Courtney Lawes has pulled out of England's training squad after picking up a calf injury playing for Northampton on Saturday.
Steve Borthwick's squad have gathered at Pennyhill Park for a training camp before their Six Nations opener with Scotland at Twickenham on 4 February.
Gloucester hooker George McGuigan has also withdrawn with a knee problem.
Lock David Ribbans comes in for his Northampton team-mate Lawes, 33, and Bath's Tom Dunn replaces McGuigan, 29.
Lawes, who can play as a lock of back row, has already missed large parts of the season through injury, including all of England's autumn Tests after suffering concussion.
At the launch of the Six Nations on Monday, Borthwick said Lawes' injury will be "scanned and investigated today to fully understand it, so he won't be joining the squad in the next few days".
The British and Irish Lions forward and Bristol prop Ellis Genge were named as England vice-captains by Borthwick after he succeeded Eddie Jones as head coach last month.
Another hooker, Jamie George, is also a concern after he was concussed during Saracens' defeat by Edinburgh on Sunday.
England have already lost Exeter number two Luke Cowan-Dickie to an ankle injury for at least the start of the Six Nations.
After their tournament opener against Scotland, England host Italy on 12 February.
A trip to Wales follows on 25 February before a home game against defending champions France on 11 March precedes their final game against Ireland on 18 March in Dublin.
The Six Nations begins a huge year in the international game, with the World Cup starting in France on 8 September.
'Borthwick's Scotland plans may now look different'
Chris Jones, BBC rugby union correspondent
Like all England head coaches before him, Steve Borthwick is dealing with a constantly changing picture as injuries put his best-laid plans to waste.
Lawes has been dogged by injury setbacks of late, but the fact Borthwick named him as a vice-captain shows how integral he remains to the squad, and while it's unknown how serious the problem is, his involvement in the Calcutta Cup looks very unlikely.
David Ribbans coming in hints that Borthwick sees Lawes as an option at lock, where he hasn't played in years, while England are now stretched at hooker with Cowan-Dickie already absent and Jamie George also an injury concern.
The team Borthwick selects for the Scotland showdown may look very different to the one he imagined a few weeks ago.
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