About 1491-
There are some estimates that put the post-Columbus pathogen die-off of Native Americans at 90-95%!
The reason later Europeans found such a boundless wilderness was because most of the people died off in the early to mid 1500s.
Note I’m not blaming the Europeans, as they really knew nothing about pathogens and microbes, fungi, and viruses. However, the Old World was a hothouse for creating all kinds of tiny toxic critters due to farm animals like pigs and fowl living in close proximity to people (like in the house itself, as is still done in parts of China).
This means things like swine and avian flu develops the ability to cross over to humans—and back to pigs and birds, very easily. And then back again with even more vigor and strength. Imagine such a flu or disease among people with zero antibodies to any of the thousands of derivatives!