Indigenous and aboriginal peoples of the Americas and Pacific died at enormous rates soon after joining the global pathogen pool in the seventeenth to nineteenth centuries from respiratory infections such as smallpox, measles, and influenza. It was widely assumed that this represented a selection process against primitive societies. Darwinian selection for specific genetic resistance factors seems an unlikely hypothesis given that some populations stabilized quickly over two to three generations. European-origin populations whose childhood was marked by epidemiological isolation also suffered high infectious disease mortality from respiratory pathogens. American soldiers with smallpox, South African (Boer) children with measles, and New Zealand soldiers with influenza suggest that epidemiological isolation resulting in few previous respiratory infections during childhood may be a consistent mortality risk factor. Modern studies of innate immunity following Bacillus Calmette-Guérin (BCG) in infancy point toward rapid immune adaptation rather than evolutionary selection as an explanation for excessive first contact epidemic mortality from respiratory pathogens.