1. Because the vast majority of them already died from smallpox well before Manifest Destiny.

2. There is still a huge amount of open space in America. In 1800, there were only 5 million citizens, compared to 323 million today.

3. Natives lived all over the continent. Europeans landed where the ocean ended.

In the specific year you state was four years before Lewis and Clark started their expedition. They would not have survived if they did not have help from most of the natives they met along the way, one of the main objectives was to document all the natives that lived there. That would have been kind of weird goal if it was all open space.

Sorry, by open space, I meant sparsely populated, not pasture land.

re point one the __lowest__ plausible percentage of North America and South Americans that died of disease before ever hearing a rumor of it source is 90% and has a fair chance of being higher, the disease front traveled as quickly as the natives, refuges from one dying village to the next, or people coming to investigate why no body has visited from the next community over in a while. The deliberate atrocities later were just a mop up action in the larger picture.

I've read estimates of smallpox outbreak at 20-50% mortality across the continent. Some areas in New England are estimated to have a 96% mortality rate. Pretty crazy.