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."

In response to COVID-19 concerns from Kamala Harris’ team, the Commission on Presidential debates has agreed to add additional safety precautions at the debate.

Vice President Mike Pence and Harris will be seated 12-feet and 3-inches away from each other and from the debate moderator, USA Today Washington Bureau Chief Susan Page. As was the case at the presidential debate, there will be no handshakes between the candidates, and while the Commission said there would also be plexiglass separating Harris, Pence and Page, the Pence campaign has objected to using it.

A senior administration official in Pence’s office told ABC News Tuesday that there had been no formal agreement about the plexiglass and that while Harris and Page could use it, Pence doesn’t want to.

In a statement to ABC News, Pence spokeswoman Katie Miller said, "If Sen. Harris wants to use a fortress around herself, have at it."

Though Harris, Pence and Page will not wear masks on stage, everyone else in the debate hall will be required to wear one. Anyone who takes their mask off will be escorted out, according to the rules.

During the presidential debate in Cleveland, members of the Trump family were seen sitting in the audience without masks, even after being asked to put them on.

Harris and Pence will be tested prior to the debate, according to the Commission, which is a change from the presidential debate when the campaigns were responsible for testing their candidates and traveling parties.

“They’ve got to wear a mask, and if they take their mask off they're gonna be escorted out, and I don't care who they are, they'll be escorted out,” said Frank Fahrenkopf, chairman of the Commission on Presidential Debates, in an interview with ABC News.

The vice president has tested negative each day since Friday, and his White House physician has cleared him from having to quarantine, citing that he is not a “close contact” with anyone who’s tested positive, including Trump.

But Pence was present at the Rose Garden ceremony on Sept. 26 when Trump announced Judge Amy Coney Barrett as his U.S. Supreme Court nominee. Eleven of the attendees have since tested positive for COVID-19. He was also in the Oval Office with Trump the morning of his debate, just days before the president tested positive.

Harris tested negative for COVID-19 Monday after being screened in Salt Lake City, where she has been gearing up for the debate, according to an aide.

-ABC News' Justin Gomez and Averi Harper