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Dr Anthony Fauci says Omicron is "raging around the world" as he warned of the increased risk posed to unvaccinated people.
President Joe Biden's chief medical officer said the new variant has an "extraordinary capability" for transmission.
He called on Americans to get their vaccines, take tests and wear face masks in a bid to mitigate the spread of COVID-19 in the lead up to Christmas.
It comes as case numbers surge in the US, especially in densely populated areas such as New York City.
Around the world, the UK has seen record numbers of daily infections over the last few days while other European countries have imposed lockdown restrictions in a bid to stem to the rise in infections.
Speaking on NBC's Meet The Press programme, Dr Fauci said: "The one thing that's very clear, and there's no doubt about this, is its extraordinary capability of spreading - its transmissibility capability.
"It is just, you know, raging through the world, really."
While he said that South African scientists say the ratio of Omicron cases to hospital admissions remains low, everyone has still "got to be careful".
Dr Fauci added: "When you have so many, many infections, even if it is less severe, that overcomes this slight to moderate diminution in severity because our hospitals... are going to be very stressed with people because, again, we have so many people in this country who are eligible to be vaccinated, who have not yet been vaccinated.
"And that's going to be a real problem for a stress on the hospital system."
The rise in cases has forced major event like sports matches and Broadway shows to be postponed and cancelled, including NBA and NHL games.
Several universities including Cornell and Harvard have also reverted back to online learning as community transmission spreads on campuses.
Dr Fauci said: "We are going to see breakthrough infections, there's no doubt about that.
"The difference between a vaccinated and boosted person who has an infection and someone who has an infection who's never been vaccinated, there's a major difference with regard to the risk of severity."
He also spoke about people travelling over Christmas, saying there is "always a risk of increased infection".
"If people need to travel and want to travel for the obvious family reasons, during this holiday season, if you're vaccinated and you're boosted and you take care when you go into congregate settings like airports, to make sure you continually wear your mask, you should be okay," he said.
Mr Biden is expected to address US citizens on Tuesday, unveiling new steps his administration is taking to combat the omicron variant.
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