By Maeve Reston, CNN

(CNN) -- Vice President Mike Pence and California Sen. Kamala Harris are squaring off Wednesday in their only debate as the Trump administration reels from an outbreak of Covid-19 at the White House and erratic decisions by the commander in chief.

In a torrent of developments since the first presidential debate last week, President Donald Trump tested positive for coronavirus, was hospitalized for treatment and then returned to the Oval Office on Wednesday after a little more than a day of isolation at home. It's still unknown when the President last tested negative for the virus. At the same time, White House aides and Trump allies are testing positive, many of the nation's top military leaders are quarantining after they were exposed to a colleague with Covid-19 and negotiations over an economic rescue package have stalled after Trump unexpectedly halted them Tuesday in a tweet.

Those developments have put Pence, who heads the White House coronavirus task force, on defense at a time when the Trump campaign desperately needs a reset. Harris is set to make history as the first Black and South Asian female Democratic vice presidential nominee to participate in a general election debate.

A crucial night

While vice presidential debates generally have not made much of a difference in the outcome of the election, voters may pay more attention to this one because of the age of the two men at the top of the ticket.

Democratic nominee Joe Biden, who is 77, won the primaries after portraying himself as a bridge to the next generation of Democratic leaders -- and Harris, 55, was seen as the embodiment of that idea when he chose her as his running mate and made her the heir apparent within the party.

The 74-year-old Trump's Covid diagnosis has focused even more attention on his age. And because of the lack of transparency from White House doctors, it is unclear whether he could face medical complications during his bout with the coronavirus. Regardless, Pence, 61, has long been viewed as one of the top Republican contenders for the White House in 2024.

Expectations are high for Harris because of her background as a prosecutor and the skills she showed when she aggressively questioned Trump's nominees as a member of the Senate Judiciary Committee. But before the primaries, when she was running for the Democratic nomination, she sometimes delivered uneven performances on the debate stage.

Pence, a former radio host, is one of the Trump administration's most effective communicators. He has also shown a far greater capacity than the President to speak with empathy and compassion for those who have been afflicted with Covid-19.

The vice president's main objective on Wednesday is to portray Harris as one of the most liberal members of that body, aiming to paint her as a vice presidential contender whose views are out of step with most Americans and someone who would steer Biden toward socialism. Pence also hopes to portray the White House's actions on the coronavirus in a positive light -- from the distribution of aid and personal protective equipment to states, to the efforts to develop a vaccine and therapeutics to treat the virus in record time.

More than a week after Americans saw a combative Trump aggressively attack Biden, cut him off and spend the debate in a confrontational posture, Pence aims to be much different. Pence is expected to abide by the rules, speak in an even-handed manner and find ways to make his points with a measured tone. Aides told CNN's Ryan Nobles that Pence is looking to "prosecute" the case against Harris and won't be afraid to return fire when given the opportunity, but the difference is he will do so with a smile.

Harris is aiming to make the debate all about Trump, the Harris camp told CNN's Kyung Lah. Harris' team expects Pence to be smooth and have a great debate but feels that the vice president's calmer demeanor doesn't make him more truthful than Trump. Fact checking won't be the emphasis, but connecting Pence as the head of the White House's coronavirus task force and how they have failed the American people is the key message, with a focus on talking to voters at home.

Tuesday's CNN/SSRS poll showed Biden opening his widest lead over Trump this cycle, 57% to 41%, after their contentious first debate in Ohio and the President's Covid-19 diagnosis. Biden has a narrower lead over Trump in the battleground states that will determine the outcome in the Electoral College.

In the wake of that poll, the Trump campaign -- and senior Republicans on Capitol Hill -- told CNN's Jeff Zeleny that Wednesday may be one of the last best opportunities to try to reset this race.

"If we don't slow the bleeding tonight, the remaining three weeks could be grim for Republicans," a Republican senator close to the White House said. "Everyone in the party knows that."

Covid at the center of the campaign

The President's Covid-19 diagnosis and the widening circle of infected aides have made the administration's reckless handling of the coronavirus the central issue of the campaign once again, and questions still surround Pence's exposure to coronavirus less than a week after Trump tested positive.

After returning from his stay at Walter Reed National Military Medical Center, the President made the false statement on social media that the coronavirus is less deadly than the flu and he has issued tone-deaf remarks about how Americans should not let Covid-19 control their lives.

The virus is still one of the top issues on the minds of Americans, who are already voting less than a month before Election Day. In recent days, Trump has slid even further behind Biden in the polls -- a nationwide CNN poll released Tuesday showed the President trailing his opponent by 16 points -- as Americans recoil from his erratic behavior and his disregard for the dangers of the virus.

Pence is being forced to answer for the President's lax handling of the virus, as well as Trump's decision to reject the advice of scientists and top medical advisers by continuing to hold rallies and events with huge crowds of supporters who did not socially distance or wear masks.

Dr. Anthony Fauci, the nation's top infectious disease expert, warned Tuesday that the US could see as many as 400,000 deaths by the end of this year if Americans do not follow health mitigation guidelines like wearing masks, a simple life-saving tool that the President has repeatedly mocked.

Cases have ravaged the White House staff, and a number of allies and advisors have fallen ill with the virus after participating in the preparations for Trump's first debate with Biden or the White House ceremonies related to Trump's nomination of Judge Amy Coney Barrett to the Supreme Court.

Pence was at the White House receptions and the Rose Garden announcement for Barrett, events that appear to have accelerated the spread of the virus at the White House. But he has repeatedly tested negative, as recently as earlier on Wednesday, and has not quarantined. He and Harris are separated during the debate by plexiglass shields, which are more than 12 feet apart.

This is a breaking story and will be updated.