Following Trump's diagnosis, as well as positive tests among several people close to the president, the Commission on Presidential Debates expanded COVID-19 safety precautions and placed Harris and Pence 12 feet apart for their debate, instead of the 7 feet originally planned. They were also separated by two plexiglass dividers.
The Trump administration's handling of the pandemic was a point of contention and the effects of the virus were discussed throughout the nine roughly 10-minute segments of the debate, which also addressed healthcare, the economy, racial injustice and the nomination of a new justice to the Supreme Court.
Harris, a Democratic senator from California, declared that the Trump administration has "forfeited their right to re-election" based on its handling of the pandemic, which has sickened more than 7.5 million people worldwide and killed more than 211,000 patients in the United States, according to data from Johns Hopkins University.
"The American people have witnessed what is the greatest failure of any presidential administration in the history of our country," Harris said.
Harris referenced Pulitzer Prize-winning journalist Bob Woodward's book, Rage, in which he wrote that Trump understood the deadly nature of the disease in early February and "played it down" to the American public, because he didn't want to "create a panic."
"Can you imagine if you knew on Jan. 28, as opposed to March 13, what they knew? What you might have done to prepare?" Harris asked.
Harris went on to question whether Americans may have felt panic in rushing to buy supplies to prepare for a lockdown, not knowing when their children would return to school and weighing the risk of spreading the virus to elderly loved ones.
Harris said she and her running mate, former Vice President Joe Biden, would provide a national plan to control the virus that's focused on contact tracing and testing and aid in the development of a vaccine and would ensure it's available to all Americans at no cost.
Pence, appointed to lead the White House Coronavirus Task Force, defended the administration's response and touted Trump's decision to cut off travel from China, where the disease originated, early in the health crisis.
He also condemned Harris' criticism of the administration as an insult to efforts of the American people and accused the Democratic candidates of copying the White House's COVID-19 response plan.
"It looks a little like plagiarism, which is something Joe Biden knows a little about," Pence said, referring to an accusation that Biden withdrew from the 1988 presidential race after on one occasion borrowing a phrase from a British politician without attribution. He had, however, properly attributed the remark on a prior occasion.
Pence also defended a Rose Garden event for the announcement of Amy Coney Barrett's nomination to the Supreme Court on Sept. 26, which has been linked to several positive COVID-19 tests among attendees.
"Many of the people who were at the event actually were tested for coronavirus and it was an outdoor event, which all of our scientists regularly and routinely advise," he said, not addressing a portion of the event that was held indoors.
Pence also said he and the president "trust the American people to make choices in the best interest in their health," while criticizing Biden and Harris for proposing mandates to curb the spread of the virus.
Harris repeated a previous declaration that she does not trust Trump's endorsement of a vaccine for the virus.
"If the doctors tell us that we should take it, I'll be first in line to take it. Absolutely," she said. "But if Donald Trump tells us to take it, I'm not taking it."
Pence accused Harris of "playing politics with people's lives" after said she would refuse a Trump vaccine.
"Your continuous undermining of confidence in a vaccine is unacceptable," he said.
The candidates offered opposing responses on whether they believe justice was done in the case of Breonna Taylor, a 26-year-old Black woman who was shot and killed by police during the serving of a "no-knock" warrant at her Louisville apartment, after just one of the three officers involved in the shooting was indicted with none being charged directly for her death.
Harris said she believed Taylor's life was taken "unjustifiably," referencing conversations she had with Taylor's family and declaring that they deserve justice.
"We're never going to condone violence. But we always must fight for the values that we hold dear, including the fight for our ideals," she said.
Leaning on her career experience as a former prosecutor, Harris laid out her and Biden's plan for police reform in response to the high-profile killings of Taylor, George Floyd and other Black people throughout the country.
"Bad cops are bad for good cops. We need to reform policing in America and our criminal justice system. That's why Joe and I will immediately ban chokeholds and carotid holds," she said.
Harris also said she and Biden will seek to eliminate private prisons and cash bail as well as decriminalizing marijuana and expunge the records of people who have been convicted of marijuana-related crimes.
Pence offered "sympathies" to Taylor's family but criticized Harris for questioning the grand jury's decision, saying he trusts the U.S. justice system.
"This presumption that you hear consistently from Joe Biden and Kamala Harris that America is systemically racist and as Joe Biden said, he believes that law enforcement has an implicit bias against minorities, it's a great insult to the men and women who serve in law enforcement."
Pence said that the Trump administration would continue to stand by law enforcement, adding that "we don't have to choose between supporting law enforcement, improving public safety and supporting our African American neighbors and all of our minorities."
Harris defended her record, noted that she was the only person on the stage with any prosecutorial experience and twice responded that she will "not be lectured" on the issue of race by Pence.
Pence said he hopes Barrett receives a "fair hearing" while she is considered for a seat on the Supreme Court to replace the late Justice Ruth Bader Ginsburg.
He also pressed Harris to answer whether she and Biden would seek to "pack" the court by appointing liberal justices beyond the total of nine that have historically served on the court.
"This is a classic case of, if you can't win by the rules, you're going to change the rules," Pence said.
Harris noted that former President Abraham Lincoln said, when a Supreme Court vacancy opened in 1864, an election year, that it should not be filled before the people vote.
Harris did not directly answer whether they would seek to appoint more liberal justices to the court but said that the Senate should not move forward with Barrett's confirmation so close to the Nov. 3 election.
"We're literally in an election. Over 4 million people have voted. People are in the process of voting right now. And so Joe has been very clear, as the American people are: Let the American people fill that seat in the White House and then we'll fill that seat in the United States Supreme Court," she said.
Pence criticized Harris for delivering a "non-answer" and again alleged she and Biden would seek to pack the court.
"Men and women, I gotta tell you, people across this country if you cherish our Supreme Court, if you cherish the separation of powers, you need to reject the Biden-Harris ticket come Nov. 3 and re-elect President Donald Trump," he said.
The fly and red eye
Pence's appearance was marked by two peculiar happenings on Wednesday -- a fly that landed on his hair and what appeared to be redness in his left eye.
The fly, clearly visible as it sat on the right side of Pence's head, remained there for a couple minutes before it disappeared -- and, of course, took on a life of its own on social media. There are several new accounts, including "Mike Pence's Fly."
The eye redness prompted a bit more concern -- with some noting that conjunctivitis, also known as pinkeye, has been reported as a potential symptom of COVID-19.
Pence spokesman Devin O'Malley said the vice president tested negative on Tuesday and Wednesday, and called speculation that he has COVID-19 "reckless."