Manning will be looking for a bit of revenge Sunday night as the Denver Broncos host the Saints, who play their first game under interim coach Joe Vitt.
A lot has changed since that matchup in February 2010. Of course, Manning is no longer donning an Indianapolis Colts uniform. And the Saints - having started 0-4 - aren't exactly looking like Super Bowl contenders, though they've won two in a row.
But other things - like Manning and Brees starring as two of the league's top quarterbacks - are still the same.
"Both guys are first-ballot Hall of Famers," said Denver cornerback Tracy Porter, whose interception return for a touchdown sealed the Super Bowl for the Saints.
Porter may not get a chance to face his former team for the first time, as he sat out Friday's practice after missing Thursday's to see a doctor about symptoms he continues to experience following a seizure he suffered in August.
Manning has silenced doubts regarding his health after missing last season with a neck injury.
The Broncos (3-3) began 1-2 as Manning compiled an 85.6 passer rating with five touchdowns and three interceptions, but Manning has since thrown for at least 300 yards and three touchdowns while completing more than 70 percent of his passes in each of Denver's last three games, becoming the first NFL player to accomplish that feat.
Manning's latest masterpiece saw him and the Broncos erase a 24-0 halftime deficit on the way to a 35-24 victory over San Diego on Oct. 15, before the team's bye week. One more game-winning scoring drive for Manning in the fourth quarter or overtime would give him 48, passing Dan Marino for the most all-time.
"He is a football genius," said Vitt, who returned this week from a suspension for his role in the bounty scandal. "He understands defenses, alignments and pre-snap reads. When you talk about the skill level of quarterbacks there needs to be three characteristics and he has all three.
"He is tough, smart and accurate. He is also one of those players, a lot like Drew, that makes other people around him accountable and makes other people around him better."
Manning benefited from the Denver defense forcing six turnovers against the Chargers, something the Saints' struggling unit could sure use after forcing just eight in its first six games.
Under first-year defensive coordinator Steve Spagnuolo, New Orleans (2-4) has surrendered 2,793 yards, the most in NFL history through six contests since at least 1950. The 30.3 points per game allowed by the Saints are the league's fourth-most.
"I'm certainly not a miracle worker," Vitt said. "I'm humble to be back here. I met with (Spagnuolo on Monday) morning, and we know there are things we can do better from a coaching standpoint and from a players' standpoint and from a schematic standpoint."
The return of Vitt - who is also the team's linebackers coach - could help, as could linebacker Jonathan Vilma. Last Sunday's 35-28 victory at Tampa Bay was Vilma's first game this season following knee surgery, and he and defensive end Will Smith will be allowed to play against the Broncos before their bounty suspension appeals are heard on Oct. 30.
For at least the time being, all of the Saints' players and coaches that received bounty-related suspensions - except for head coach Sean Payton - are with the team again. Even though Vilma was limited in the amount of snaps he played last weekend, teammates said his return provided an emotional lift.
"Jonathan Vilma is the epitome of team player and an inspirational guy that I think all the guys kind of feed off," Spagnuolo said. "I'm sure glad we got him back."
The Saints offense has been clicking, with New Orleans totaling 66 points in its back-to-back wins. Brees has thrown for a combined eight touchdowns in those games, extending his NFL record for consecutive games with at least one TD pass to 49.
Denver may need a better start to keep up with the high-powered Saints. The Broncos have generated just 42 first-half points this season, instead largely relying on a plus-73 scoring differential in the fourth quarter - the second-highest in NFL history for a team's first six games.
"We're studying it and trying hard to get off to a better start," Manning said. "This would be a great week to do it. This is not a team you want to fall behind because they have potential to keep scoring, keep extending that lead."
Brees' teams have lost all four of his games in Denver, including a 34-32 defeat when the Saints visited four years ago.
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