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The US president laid out plans for sweeping new Covid measures which require employees at large companies to be vaccinated or face weekly testing.
Two thirds of the country’s workforce will be impacted by the change which is part of a broader and more aggressive attempt to get Americans vaccinated amid the country’s fast-spreading delta variant.
This includes more than 17 million healthcare workers at hospitals and other facilities receiving federal benefits.
“We’re in a tough stretch and it could last for a while. We can and will turn the tide on Covid-19,” Mr Biden said.
Speaking from the dining room of the White House, Mr Biden unveiled the strategy on Thursday with hopes of reassuring Americans tiring of the pandemic.
Despite a campaign urging all those eligible to get free vaccines, just some 53% of Americans are fully vaccinated - according to data from the US Centers for Disease Control and Prevention.
The disease has killed more than 654,000 people in the States.
Mr Biden’s speech also covered mask-wearing, protecting the economic recovery from the pandemic-induced recession and improving healthcare for those infected with Covid.
His new mandate triggered an immediate backlash from Republican opposition who say the government should not be involved in individuals’ health decisions.
In the coming weeks, the US labour department’s Occupational Safety and Health Administration (OSHA) will issue its rule for private companies to require vaccines or tests.
Action will be taken against those that did not comply and substantial fines of nearly $14,000 could be handed out per violation.
All federal employees, previously required to be vaccinated or get tested, now have 75 days to get the jab or face losing their jobs unless they are exempt.
The administration also plans to ramp up testing capacity for the virus.
Big retailers - including Walmart, Amazon.com and Kroger - will sell the tests at cost for the next three months to make them more affordable, the officials said.
Critics have said the Biden administration has not done enough on testing during its seven months in office.
The full recovery of the US economy depends on blunting the spread of the virus which is a key health and political goal of the president who entered the White House in January.
“Our overarching objective here is to reduce the number of unvaccinated Americans,” White House spokeswoman Jen Psaki said, noting 80 million still have not been vaccinated.
“We want to reduce that number, decrease hospitalizations and deaths and allow our children to go to school safely.”
Federal workers unions suggested on Thursday they would accept the vaccine mandate.