So, Native Americans, like all humans who aren't immunocompromised, have both an innate and adaptive immune response that protects them from infectious organisms. Once exposed to a novel pathogen, their bodies, like all the rest of us, start a cascade of immunological messages and defenses to combat the new disease. If successful they, like the rest of us, will carry the memory of how to defend against that infectious organism, and mount a better response the next time around. There is no reason to suspect some form of biological inferiority limits their ability to respond to pathogens. As I dive into below, however, the processes of colonialism consistently created an unhealthy world for Native Americans, and that (not immunological weakness) accounts for differential mortality due to epidemic disease. We still see those pressures today, with increased morbidity and mortality due to Covid-19, because we still live in a structurally violent, unhealthy world.

The root of your question might have several key flaws in understanding of the history of the Americas. I'll address those below, before talking about the active creation of an unhealthy world.

First, there is a persistent myth that the New World was some kind of disease-free paradise until the arrival of Europeans. New World populations played host to a wide variety of intestinal parasites (roundworm, hookworm, whipworm, etc.), gastrointestinal diseases (Giardia, Entamoeba, and Cryptosporidium, etc.), Chagas disease, syphilis, Rocky Mountain Spotted Fever (and possibly Lyme), and tuberculosis. I also hypothesized they would be subject to occasional zoonotic events (when a non-human pathogen jumps into human hosts), just like modern populations with frequent access to wildlife/bushmeat trade. There is also reason to believe that observed epidemics that occurred after contact, like the cocoliztli (a Hanta Virus-like hemorrhagic fever) epidemics that swept through Mexico in the sixteenth century, were present, though perhaps more contained, before contact. Two cocoliztli epidemics, in 1545 and 1576, killed between 7 and 17 million people in highland Mexico, Europeans included. There is no evidence the pathogen responsible for the epidemic arrived from the Old World, but researchers suspect a massive drought altered the relationship between the murine host and humans, leading to increased chance of pathogen transmission, and a catastrophic epidemic. New research has muddied the cocolitzli argument, however, after the discovery of Salmonella enterica in contact period mass burials.

Second, there is a persistent myth that disease wiped out ~90% of Native American populations in the years immediately surrounding contact. The 90-95% figure that dominates the popular discourse has its foundation in the study of mortality in conquest-period Mexico. Several terrible epidemics struck the population of greater Mexico (estimated at ~22 million at contact) in quick succession. Roughly 8 million died in the 1520 smallpox epidemic, followed closely by the 1545 and 1576 cocoliztli epidemics where ~12-15 million and ~2 million perished, respectively (Acuna-Soto et al., 2002). After these epidemics and other demographic insults, the population in Mexico hit its nadir (lowest point) by 1600 before slowly beginning to recover.

Though the data from Mexico represents a great work of historic demography, the mortality figures from one specific place and time have been uncritically applied across the New World. Two key factors are commonly omitted when transferring the 90-95% mortality seen in Mexico to the greater Americas: (1) the 90-95% figure represents all excess mortality after contact (including the impact of warfare, famine, slavery, etc. with disease totals), and (2) disease mortality in Mexico was highest in densely populated urban centers where epidemics spread by rapidly among a population directly exposed to large numbers of Spanish colonists. Very few locations in the Americas mimic these ecological conditions, making the application of demographic patterns witnessed in one specific location inappropriate for generalization to the entire New World.

The myth of catastrophic disease spread often cites an incredibly high case fatality rate (number of people infected who die of that disease) for introduced pathogens in the Americas. We hear that an infectious organism like smallpox, which historically has an overall fatality rate of 30%, killed 95% of infected Native Americans. Taken without reference to the greater ecological situation, and assuming the validity of colonial mortality rates (a large assumption), the myth arises of an immunologically weaker Indian population unable to respond to novel pathogens.

Examining the greater context reveals how the cocktail of colonial stressors often stacked the deck against host immune defense before epidemics arrived.

For example, the indigenous slave trade destabilized the U.S. Southeast. When attacks by slavers disrupted normal life, hunting and harvesting outside the village defenses became deadly exercises. Nutritional stress led to famine as food stores were depleted and enemies burned growing crops. Displaced nations attempted to carve new territory inland, escalating violence as the shatterzone of English colonial enterprises spread across the region. The slave trade united the Southeast in a commercial enterprise involving the long-range travel of human hosts, crowded susceptible hosts into dense palisaded villages, and weakened host immunity through the stresses of societal upheaval, famine, and warfare (Kelton). All of these factors were needed to propagate a smallpox epidemic across the Southeast, and all of these factors led to increase mortality once the epidemic arrived. Likewise, Plains Winter Counts recount disease mortality consistently increased in the year following nutritional stress (Sundstrom), and this link was understood by European colonists who routinely burned growing crops and food stores when invading Native American lands, trusting disease and depopulation would soon follow (Calloway). Mortality increased in populations under nutritional stress, geographically displaced due to warfare and slaving raids, and adapting to the breakdown of traditional social support systems caused by excess conquest-period mortality. Context highlights why many Native Americans, like modern refugee populations facing similar concurrent physiological stress, had a decreased capacity to respond to infection, and therefore higher mortality to periodic epidemics.

Not to break the twenty year rule, but we still see how the construction of an unhealthy world (lack of access to clean running water, lack of access to electricity, poor health care access, increased comorbidities, etc.) influences mortality to a novel pathogen. Native Americans, like other minority populations in the United States, suffered higher Covid-19 mortality rates than their white neighbors.

To sum up, any individual would begin mounting an immune response once they encountered a novel pathogen. The population as a whole would reach herd immunity once a sufficient number of individuals acquired immunity to the new disease. There is no reason to think these fundamental processes were somehow biologically inhibited for indigenous peoples in the Americas. The construction of an unhealthy environment, however, places any population under stress and limits their ability to rebound from infectious organisms. If we inherit a myth of catastrophic disease mortality after contact, and ignore the larger environmental picture, we may subconsciously internalize a story of indigenous biological and immunological inferiority. This would be a great disservice not only to our understanding of the past, but also our commitment to serve our neighbors in the present. The realities show a far more complex picture, one common to all biological organisms since the beginning of life on this planet; host and pathogen and environment all interacting in a dynamic, ever-changing biological arms race.

Sources:

Acuna-Soto et al., (2002) “Megadrought and Megadeath in 16th Century Mexico”

Beck Chiefdoms, Collapse, and Coalescence in the Early American South

Calloway One Vast Winter Count: The Native American West before Lewis and Clark

Etheridge & Shuckhall, editors Mapping the Mississippian Shatter Zone: The Colonial Indian Slave Trade and Regional Instability in the American South

Kelton Epidemics and Enslavement: Biological Catastrophe in the Native Southeast 1492-1715

Sundstrom (1997) “Smallpox Used Them Up: References to Epidemic Disease in Northern Plains Winter Counts, 1714-1920.”