He's calling for "vigilance" from all parties, though the league will institute some new measures in the coming days.
"I think the vast majority of our players have done a really good job adhering to what are difficult protocols," Manfred told ESPN.com on Wednesday morning. "They're contrary to the way people normally live their lives.
"Relatively small deviations from the protocols can cause serious problems. That's a reality. ... Any individual act, you say, 'Wow, not a big deal,' but those individual acts can cause problems."
The commissioner said the spread of the virus throughout the Marlins and Cardinals -- causing both teams to shut down for a period of time -- can be traced back to lapses in the protocols.
"We believe, in the two serious outbreaks, that we can identify deviations from the protocols that resulted in the situations that we had," Manfred stated. "The key is vigilance. It's vigilance on the part of the commissioner's office, club officials, players and everyone involved in the game."
Manfred said the league is taking steps to ensure safety of its players, even more, while "re-emphasizing" and even tweaking its most important protocols.
• Masks: Teams will upgrade to surgical masks on planes. Previously, cloth masks were deemed usable, but some spread within the Marlins and/or Cardinals is believed to have occurred on charter flights, according to sources.
• Planes: There will be an even more aggressive stance about managing social distancing on planes.
"We have to make sure people stay in their seats," Manfred said.
• Eating: While eating and drinking still won't be banned on planes, it's strongly encouraged to do so in a timely manner and in staggered times. Players in the same row shouldn't both have their masks down.
• Outdoor space: "We're going to re-emphasize the significance of outdoor space. Everybody has built outdoor space adjacent to clubhouses."
• Bullpens: "Another issue," Manfred said. "Bullpens aren't big by design. We need to be taking advantage of the opportunity presented by not having fans in the ballpark and spread those relief pitchers out." Sources indicate this is another area in which spread could have occurred within the Marlins or Cardinals.
Later on Wednesday, the league sent a lengthy memo, a copy of which was obtained by ESPN, to teams outlining Manfred's points and other changes to its 2020 operations manual.
Manfred said there was discussion about testing more often, perhaps every day.
"We have thought about it," he said. "The advice we're getting from our medical experts is that the additional benefit from testing every day is really, really small due to the incubation period."
The Marlins, in particular, were a good test case regarding incubation of the virus. There were players who tested negative for several days before testing positive again. It's why the commissioner believes the league has done the right thing with Miami and St. Louis by canceling games until several negative tests came back for the uninfected.
Immediately calling up players from the taxi squad and taking the field with the healthy players would not account for incubation.
"We learned from both the Marlins and the Cardinals, when you're aggressive about taking games down, and getting through that period of time until you don't have any more positive tests, there's benefits long term to keeping the season moving," Manfred said. "We are encouraged by the fact that we've never had cross-contamination from one team to another. We're hoping that the trend continues."
Manfred confirmed the 28-man roster will be permanent beginning on Thursday, emphasizing the league and players' association came together on the issue once the players brought it up. He wouldn't address specific plans for the postseason but acknowledged that a pivot from how things are currently being done might be necessary. Neutral-site games have always been a possibility.
"We've begun the process of talking about what changes could be made to allow us to continue to play," Manfred said of October baseball. "We pay attention to the experts. We know that the fall could be a little different."
Asked whether there would be a minimum number of games that need to be played by a team to qualify for the playoffs, Manfred responded, "I don't have a number in my head. Flexibility remains the order of the day."
As for the rule changes, he believes the extra-inning rule, where a runner starts on second base to begin the 10th inning, has been better received than perhaps anyone thought before the season began
"We did the rule this year for health-related reasons," Manfred said. "I know there's a lot of theories out there that I've been itching to get this rule into the big leagues. That's really not the case. I do think people have found it to be exciting."
Before his discussion with ESPN, Manfred had been on the phone with his medical experts, who continue to stress that need for vigilance. It's a word that came up often.
"I recognize, the owners recognize, these protocols are really detailed," Manfred said. "The vast majority of players are working hard to adhere to them. That's why we have 28 clubs that have been darn good, but because we had two outbreaks that had small deviations, that doesn't mean the protocols are bad. The protocols remain viable as a mechanism to keep our players safe."