The advance of smallpox from Mexico in to California shows it preceded mission establishment.
There is no uncontested evidence for any sort of European disease in California before the Spanish invasion. The idea of California as an "island" insulated from the colonial disease pool was always the historical consensus, and though William Preston has questioned it, he offers no substantive evidence that Precolonial California suffered from disease, only that it
could have.
Scattered missions in Northern Mexico, and California and the American Southwest were perfectly adequate be be starting lines for disease.
It is true that disease IOTL spread beyond the European frontier in the seventeenth and (especially) eighteenth centuries. There is no real evidence that they did so in the sixteenth century (even the idea that the Inca died of smallpox is conjecture, since colonial sources only vaguely refer to some sort of "plague" and we know the population centers of the Americas did have some sort of infectious disease before 1492 -- several were circulating in Maya country, for example), before European influence profoundly influenced the entirety of the Americas. By the eighteenth century, most of North America was already profoundly destabilized by the Indian slave trade, the Iroquois wars and the resulting depopulation of the entire Great Lakes region, and the spread of the horse. These were all factors absent in the earliest days of Contact.
Also, despite a major smallpox epidemic in 1837 that killed half the population of the Plains (and various other epidemics documented in the Winter Counts), the Lakota population
quintupled between 1804 and 1850, from 3,000 to 14,000, thanks to success in warfare and resulting high nutrition and fertility and low mortality under normal conditions. By contrast, their victims almost disappeared because defeat at the hands of the Sioux made their general living conditions worse and increased the impact of disease. So, just as the case of Jesuit Paraguay shows, terrible epidemics were not a permanent halt to population growth; social conditions needed to back it up.
once it reaches the "virgin soil" the effect will be the same.
The "Virgin Soil" hypothesis is no longer consensus; disease killed as many as it did only because indigenous social structures were so profoundly disrupted by invasion and conquest (whether by Europeans or, as in the case of the Lakotas' victims, by indigenous peoples armed with European guns and horses). Look at Livi-Bacci's work on Hispaniola (where the
encomienda system made the Taino population demographically unsustainable, with an horrifyingly low fertility, before the first smallpox epidemic) or the recent anthology
Beyond Germs: Native Depopulation in North America.
Furthermore, to the extent the relative genetic uniformity in Native Americans and inadequate immune response to these pathogens is a factor
Yes, a factor extremely exaggerated by pop historians like Mann. To
quote Jones, Crosby, the original formulator of the Virgin Soil hypothesis, "actually downplayed the 'genetic weakness hypothesis' and instead emphasized the many environmental factors that might have contributed to American Indian susceptibility to Old World diseases, including lack of childhood exposure, malnutrition, and the social chaos generated by European colonization." Research on recently contacted tribes in the Amazon suggest normal immunological responses to most modern pathogens other than tuberculosis (which is likely because of intestinal parasites that plague most indigenous populations in the Amazon, not a genetic failure). Also, new DNA markers suggest Native Americans were rather more genetically diverse than we thought.