Although considerable trade occurred within North America and Mesoamerica (and some trade with South America) before the European conquest, the population of the New World had only a few brief contacts with the population of the Old World. All these contacts involved the Vikings, a high-latitude population quite isolated from the rest of European society and thus not susceptible to European diseases.
Europe itself had suffered mightily at the hands of disease, particularly during the terrible fourteenth century, which brought the Little Ice Age, Great Famine, and Black Death. The Black Death remains probably the second deadliest plague in world history, eclipsed in sheer number of fatalities only by the 1918 Spanish influenza. These calamities radically reduced the European population and effectively ended the relative prosperity of the High Middle Ages.
The great mound builders in America might have suffered internal strife and problems associated with shifting climates. Most historians believe that native societies began to decline somewhat before European contact. But that constant contact brought terrible diseases that assumed epidemic proportions if they spread beyond their ports of entry. Because the native populations had almost no prior contact with European or Asian societies for the previous several thousand years, this repeated disease exposures surely decimated native societies even more than similar diseases ravaged Europe.
Perhaps we can find somewhat of an analogy in the 1918 Spanish influenza. The disease killed hundreds of thousands of Americans; however, it claimed perhaps one hundred million lives globally. India lost fully five percent of its population despite significant exposure to European diseases over the previous century. Perhaps the worst-affected place was tiny Brevig Mission, Alaska, which lost 85% of its population--mostly Eskimos with almost no exposure to the diseases of temperate urban Western civilization.
And let us not forget that the Europeans brought numerous dreaded diseases with them, often simultaneously, not just a single disease like the terrible Black Death or Spanish influenza. People who successfully fight one disease might remain physically and mentally weakened years after beginning recovery and struggling with grief over the loss of family. The more debilitating diseases would leave many disabled individuals who could not contribute to the agricultural economy, leading to famine. Weak persons with compromised immune systems and weakened or damaged organs frequently fall victim to disease. Native American populations could not develop immunity to every European disease without first contacting all of them, with the possible exception of smallpox, for which an inoculation (vaccine) existed.
Historical Review: Megadrought And Megadeath In 16th Century Mexico