Scrum-half Ben Youngs says a lack of recent match practice could cause England some "teething problems" in their Six Nations opener with Scotland.
Five Saracens players are selected, with number eight Billy Vunipola the only one to have played since December.
Youngs says England are not expecting it to be "all plain sailing" at Twickenham.
"A lot of us have not played for the best part of a month to five weeks," Youngs told BBC Radio 5 Live.
In a disrupted Premiership season, five matches have been cancelled following coronavirus outbreaks, while most of the England players were last involved in their club's top flight campaign on 9 January.
Youngs added: "So often as English players, we go into these tournaments having played a huge amount of European or domestic club games.
"This tournament we're going in unbelievably fresh because you haven't had that load, although you do miss that match sharpness.
"You can do all the fitness in the world, but as people say, there's nothing like actually playing the game."
England are defending Six Nations champions and Scotland have not won at Twickenham since 1983, but the latest instalment of the Calcutta Cup will be played without spectators because of the Covid-19 pandemic.
The fixture will mark the 150th anniversary of the sides' first meeting, and Youngs says the empty home of English rugby will "feel like a neutral venue".
"It does have a different feel to it," he added. "We haven't got 80,000 supporters right behind us.
"It's a shame the stadium can't be full. It will feel like a neutral venue at times, but I think it makes for a very exciting game. Both nations have got an opportunity to hopefully lift their country."