Leicester City said they had a request to postpone Thursday's game against Tottenham Hotspur rejected by the league.
The Premier League postponed Burnley's game against Watford on Wednesday after a COVID-19 outbreak in the visiting team as the possibility of festive fixture chaos loomed.
Earlier on Wednesday, Leicester City said they had a request to postpone Thursday's game against Tottenham Hotspur rejected by the league, as English football continues to face potential disruption from the spread of COVID and the Omicron variant.
The decision to call off the match at Turf Moor came just two and a half hours before the scheduled kickoff time.
"The decision was taken following guidance from medical advisers due to an ongoing COVID-19 outbreak within Watford’s squad. As a result, the club has an insufficient number of First Team players available to fulfil the match," the Premier League said in a statement.
The Premier League's rules state that if a team cannot raise 14 players then a game can be postponed although other factors, such as impact on preparation and whether or not there has been an 'uncontrollable outbreak' are also taken into account.
"In considering any application to postpone, the Board considers a range of sporting and medical factors. Each decision is taken on a case-by-case basis with everyone’s health of utmost importance," the league added.
Manchester United's scheduled game at Brentford on Tuesday was postponed after United closed their training ground due to COVID cases.
Tottenham Hotspur's Europa Conference League game against French club Rennes on Dec. 10 was also called off after a COVID outbreak in the Spurs camp.
In England's second tier Championship, Saturday's matches between Reading and Luton Town and Millwall and Preston North End have been postponed because of cases of the coronavirus.
Leicester manager Brendan Rodgers said his team had nine players out due to COVID-19 and "other medical issues", adding that the integrity of the competition is at stake in what is a "testing time of the year" with teams often playing at least twice a week.
"Unfortunately for us, we weren't granted any dispensation, which was disappointing," Rodgers told reporters on Wednesday.
"We've wanted to support the measures, but when we wanted support for the extreme situation we were in, it's disappointing not to get the support. We were touch and go for the Newcastle (United) game.
"We have had injuries since then, because we can't rotate the squad because of COVID. It's a really challenging time for us.
"We've got five games in 13 days, it's a challenging fixture list when you have a full squad, but with the numbers we have, it's extremely challenging."
The league said on Monday that between December 6-12, 3,805 players and club staff were tested for COVID-19 with 42 new positive cases discovered -- the highest weekly figure since data began being reported in May 2020.
Spurs also have issues of their own with manager Antonio Conte saying only 16 players, including youngsters, trained on Wednesday.
Tottenham's training ground has now re-opened to the first team, but Conte said it has been a difficult period.
"We had Thursday, Friday and Saturday without any sessions. Sunday we started again to work with not many players, because we also had problems with U23s," the Italian said.
Liverpool manager Juergen Klopp gave his backing to efforts to encourage widespread vaccination and the return of stricter COVID protocols across football.
"The whole vaccination thing is a massive question of loyalty, solidarity and togetherness. We have a chance to help not only ourselves but other people as well," said the German, ahead of his team's match on Thursday against Newcastle United.
"It is important to support the measures... The vaccination status of the team is quite good. Hopefully we can do it with the whole team," he said.
The Premier League last released data on vaccination levels of players in mid-October saying 81% of players had received at least one COVID-19 vaccination dose with 68% double vaccinated.
The league has reverted to 'emergency measures' put in place earlier in the pandemic with daily lateral flow testing and twice weekly PCR tests.
While there has been no move to limit crowd sizes, supporters will be denied entrance to stadiums if they cannot produce their COVID pass, showing fully vaccinated status, or a negative test result from within the previous 48 hours.
Spot checks will take place outside grounds with around 20% of fans expected to be asked for proof of their COVID status.