England will be without two of their most experienced forwards for the Six Nations with Joe Launchbury and Joe Marler both ruled out, the Rugby Football Union (RFU) confirmed in a statement on Monday.
Launchbury, a second-row, misses out due to a fibia stress fracture, while prop Marler has opted out due to personal reasons.
England coach Eddie Jones has called in Bath's Charlie Ewels for Launchbury and uncapped Wasps loose-head Tom West for Marler.
The news comes as a significant blow for England, with Jones already without loose-head prop Mako Vunipola, who is recovering from an Achilles injury.
Marler's decision to withdraw was down to wanting to be with his family, with the country in lockdown due to COVID-19.
"Always grateful for the opportunity so not an easy decision, but want to do right by my family in these crazy times and won't be meeting up with the squad for this tournament. Look forward to watching the team rip in. Go well," he tweeted.
Launchbury -- who has 65 England caps -- has been superb for Wasps this season but the injury keeps him out for the entire championship.
England start their Six Nations preparations this week at St George's Park -- the Football Association's national football centre.
Jones will miss the start of their training camp as he is self-isolating after forwards coach Matt Proudfoot tested positive for COVID-19.
They open their championship campaign against Scotland on Feb. 6 with England looking to win their fourth Six Nations title under Jones.