Former Chicago Mayor and ABC News contributor Rahm Emanuel said that the night's debate, although also important for the 2020 race, is also "first debate of 2024."

"I would call this the first vice presidential debate of 2020," Emanuel said. "And the first debate of 2024, because they're auditioning for that post."

An hour ahead of the debate, ABC News learned the coronavirus outbreak has infected "34 White House staffers and other contacts" in recent days, according to an internal government memo, an indication that the disease has spread among more people than previously known in the seat of American government.

ABC News "World News Tonight" Chief Anchor David Muir said the news presents an additional hurdle for Pence as the Trump-Pence team faces an uphill battle in the polls.

"He's the head of the coronavirus task force and he will have to make the case tonight that the American people are supposed to be able to look to this White House -- look to Vice President Mike Pence -- to keep them safe, knowing full well the president is positive, 34 people around him are positive," Muir said.

"And we also know the president will be watching tonight. He knows where the polling is right now, and he's expecting a command performance for Mike Pence to help with these numbers," he added.

ABC News Chief Political Analyst Matthew Dowd told "ABC News Live Prime" that the pressure is on Pence Wednesday night as it’s uncertain whether the public will see more presidential debates in light of the president’s positive diagnosis.

“That's the concern for Trump-Pence is that this may be the last opportunity they have in this kind of setting to present their argument to the American public,” he said. "But Kamala just has to keep things going."

Dowd, who prepped former Vice President Dick Cheney for his debate in 2004, said it's Pence’s job tonight to ensure the Trump-Pence campaign doesn’t lose any more ground.

“This is a debate that, in order for Donald Trump and Mike Pence to get back in this race where they're significantly behind, Mike Pence at least has to stop the bleeding in the polls that are going on right now,” said Dowd.

“November 3 is the end of the election, so he has to begin to start chipping away at that lead and present the Donald Trump case in a much more forceful way of why they should get another four years,” he added, noting early voting is underway in several states.

For Harris, Dowd said, it’s her first big introduction to the American people, and her goal should be to keep the momentum going.

"They don't have to build on a lead. They already have a lead it's just to keep the momentum going because we have no idea whether we're gonna have another presidential debate next week or at all,” he said.

ABC News' Chief Congressional Correspondent Mary Bruce told ABC News Prime Anchor Linsey Davis about what precautions will be in place at Wednesday night's event amid the coronavirus pandemic and what to expect from both candidates on the debate stage.

"The candidates will both be seated behind Plexiglass more than 12 feet apart," Bruce said.

Both Pence and Harris have tested negative for the coronavirus, and even as the outbreak at the White House grows, Pence's team says he is safe to debate. Bruce also explained how Pence and Harris have been preparing for tonight's debate. Harris will rely on her background as a former prosecutor.

"Despite the fact that she is known for those pointed questions her team says don't expect her to eviscerate Mike Pence," Bruce said. "She is going to try though, to speak directly to the American people that's a strategy that we saw Joe Biden use last week."

Pence will rely on his background and experience on the debate stage. Mary Bruce warns that Pence will go after Harris, and expects Pence to paint Harris as a far left candidate, a common line of attack from the Trump campaign.

"He does have a lot of experience on a debate stage," Bruce said. "He is a skillful communicator actually former television hosts, so he has much more experience in this arena."