Trump tweeted in support of Pence saying he is, "doing GREAT" and Harris, calling her a "gaffe machine," a criticism he uses often to attack her running mate Joe Biden.

Biden has also tweeted in support of his running mate during the debate, saying that Harris is "showing the American people why I chose her as my running mate."

In speaking to American leadership, Pence brought up the case of Kayla Mueller, a humanitarian worker from Arizona who was kidnapped by the Islamic State in Syria in 2013 and died in the terror group's custody.

Mueller's parents were in the debate's audience as Pence's guests and appeared last month at the Republican National Convention.

Pence suggested former President Barack Obama and Biden carried blame for Mueller's death, saying they "hesitated for a month" while she was held captive.

Harris, in her response to the topic of American leadership, first addressed Mueller's family.

"First of all, to the Mueller family, I know about your daughter's case and I'm so sorry. I'm so sorry. What happened to her is awful and it should have never happened," Harris said. "And I know Joe feels the same way. And I know that President Obama feels the same way."

In a discussion of foreign policy and the role of American leadership, Harris brought up Trump’s handling of the Iran nuclear deal and criticized the president's “unilateral” approach.

“He's walked away from agreements,” she said. “We were in the Iran nuclear deal with friends, with allies around the country. And because of Donald Trump's unilateral approach to foreign policy, coupled with his isolationism, he pulled us out and has made America less safe.”

“So, Susan, it's about relationships and the thing that has always been part of the strength of our nation, in addition to our great military, has been that we keep our word,” she added. “But Donald Trump doesn't understand that because he doesn't understand what it means to be honest.”

On the issue of jobs, Harris took aim at the Trump administration trade policy with China.

“You lost that trade war. You lost it. What ended up happening is because of a so-called trade war with China, America lost 300,000 manufacturing jobs,” Harris said. “Farmers have experienced bankruptcy because of it. We are in a manufacturing recession because of it.”

Pence responded by criticizing Joe Biden’s record on China, calling him, “a cheerleader for communist China.”

“When Joe Biden was vice president, we lost 200,000 manufacturing jobs and President Obama said they were never coming back,” Pence said.

In light of President Trump's positive COVID-19 diagnosis and subsequent concerns from Harris' team, the Commission on Presidential Debates agreed to add additional safety precautions to Wednesday's debate at the University of Utah.

Unlike last week's presidential debate, everyone in the audience will be required to wear a face mask or covering and those who don't will be escorted out of the venue.

"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," Frank Fahrenkopf, chairman of the Commission on Presidential Debates, told ABC News.

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

And the candidates will be separated by more than just the issues -- or at least one of them will be.

After Pence's close proximity to others who have tested positive for COVID-19, the Harris campaign requested plexiglass barriers be used at the debate and the commission agreed -- but the Pence campaign said Tuesday that they never agreed to a plexiglass partition.

A senior administration official in Pence's office told ABC News Tuesday that the CPD decided to publicize the new safety protocols before any formal agreement was made and that the moderator and the Harris campaign can do as they want, "but we do not."

The official said Center for Disease Control and Prevention guidelines recommend plexiglass whenever 6 feet of separation isn't possible, but noted the candidates will be 12-feet apart on stage. The comment fell in line with Pence's chief of staff Marc Short who told The Washington Post Tuesday that plexiglass is "not needed."

Pence's communications director, Katie Miller, who tested positive for COVID-19 in May, also responded to the request in a statement to Axios earlier this week saying, "If Sen. Harris wants to use a fortress around herself, have at it."

Following news that Miller's husband, senior Trump aide Stephen Miller, tested positive for the coronavirus, she reportedly left Utah and a spokesperson declined to comment if Pence would agree to plexiglass.

-ABC News Justin Gomez, Averi Harper and Ben Gittleson