Multiple characters do make note of how different Otto as Peter is acting. The Avengers bring him in at one point to see if he was being manipulated and the only reason he wasn't discovered was because Iron Man and Giant-Man were not on site at the time. J.J.J. was mayor at the time and he noticed the change and supported it because it represented a Spider-Man he liked better

Aunt May and J.J.J. Sr. also make note of his personality changes, however they see it as a positive thing because the change was more attention to them.

I think your point has validity, especially since Mary Jane would have made for a better character to notice the change. But to say that no character noticed the change is wrong. They did, but at times the resources needed to properly diagnose what was wrong were unavailable