(CNN) More than 60 million Americans are under winter storm advisories, watches and warnings, from northern Georgia to New England, as a powerful nor'easter takes aim at the East Coast.
The storm is forecast to strike most of the eastern coast Wednesday into Thursday, and several feet of snow and heavy ice could cause power outages throughout the region.
Boston and New York could see as much as a foot of snow, while parts of the tri-state area could see up to 16 inches.
"Confidence is high that this winter storm will result in significant impacts, including travel disruptions and power outages across much of the mid-Atlantic and southern New England," the Weather Prediction Center said.
Pennsylvania Gov. Tom Wolf signed disaster emergency proclamation as the state prepares for the first big storm of the winter. In New York, Mayor Bill de Blasio warned that residents need to prepared for what could be the biggest storm in several years.
Wind gusts as strong as 50 mph could also hit the coast of New England, according to the National Weather Service in Boston.
The storm system is moving out of the Rockies through Tuesday, bringing snow into the southern Plains before meeting cooler air farther east.
Freezing rain will fall along Interstate 80 and in the mountains of Virginia, with ice accumulation of more than a quarter of an inch possible in Roanoke and Charlottesville, and west to Beckley, West Virginia.
Track the storm's path and see how much snow will fall >>>
A mixture of precipitation will stretch from North Carolina to Pennsylvania, with heavy snow throughout the tri-state area and New England, maps from the Weather Prediction Center show.
Lighter snow accumulations from Indiana to New Hampshire are expected by Wednesday, the center said.
Blustery wind conditions will also be a concern, with some areas, especially along the coast, coming close to blizzard conditions. Sustained winds of 25 to 35 mph are possible, with gusts as high as 45 mph at times.
The weather could make travel very difficult or even impossible in some areas, the National Weather Service said.
The New York City Emergency Management Department issued a hazardous travel advisory for Wednesday afternoon, warning that the "heavy snow and breezing conditions could cause near-blizzard conditions."
While the storm isn't expected to have major impacts on the distribution of the Covid-19 vaccine, shippers have made contingency plans to account for weather issues.
The winter snowstorm will hit parts of the mid-Atlantic into New England beginning Wednesday, when shippers are scheduled to make 66 deliveries nationwide. Later in the week, other vaccines will be shipped in Pfizer's distribution boxes requiring dry ice.
FedEx doesn't expect any "significant impact" to service, company spokeswoman Shannon Davis wrote in an email Monday, adding they will continue to monitor the forecast.
"We have a team of 15 meteorologists monitoring conditions 24/7, and we have contingency plans in place should we see any severe weather," she said.
UPS, which has an in-house team that monitors the weather, didn't immediately respond to CNN's request for comment.
Operation Warp Speed's Gen. Gustave Perna told reporters Monday that his group plans for many different issues, with the worst-case scenario being an accident of a delivery vehicle or aircraft. Bad weather falls in the middle of the spectrum of problems, he said.
Some doses will be held in a "safety stock" should there be an issue.