LAUSR

Significance Epidemiologic data consistently show strong protection for young children against severe COVID-19 illness. Several mechanisms have been proposed to explain this phenomenon, including cross-reactive immunity—in which prior exposure to non-SARS-CoV-2 coronaviruses that commonly infect children confers some resistance to severe COVID-19 illness. We identified 3,126,427 adults (24% [N = 743,814] with children ≤18, and 8.8% [N = 274,316] with youngest child 0–5 years) to assess whether parents of young children—who have high exposure to non-SARS-CoV-2 coronaviruses—may also benefit from potential cross-immunity. In a large, real-world population, exposure to young children was strongly associated with less severe COVID-19 illness, after balancing known COVID-19 risk factors. This epidemiologic signal suggests endemic coronavirus cross-immunity may play a role in protection against severe COVID-19 outcomes.