Protective Association of Endemic HCoV-NL63 With Symptomatic COVID-19 in a Pediatric Cohort

BACKGROUND: Children experience lower rates of symptomatic and severe coronavirus disease 2019 (COVID-19) than adults, potentially due to cross-reactive immunity from prior endemic human coronavirus (HCoV) infections. However, epidemiologic longitudinal evidence supporting this mechanism in children remains limited. In 2021, outbreaks of HCoV-NL63 and HCoV-OC43 occurred in Furano, Japan. METHODS: This prospective longitudinal cohort study was conducted at a single hospital in Furano. The primary outcome was time to onset of symptomatic COVID-19. Children with HCoV-NL63 (weeks 1-21) or HCoV-OC43 (weeks 22-33) infections were compared with children infected with other respiratory viruses. Analyses included Kaplan-Meier estimation, log-rank tests, and multivariate Cox regression. RESULTS: A total of 237 children were followed for up to 700 days. Cumulative incidence analyses demonstrated a significantly reduced risk of symptomatic COVID-19 in the HCoV-NL63 group through day 700 ( P = 0.03), whereas no protective effect was observed for HCoV-OC43. In multivariable analyses, prior HCoV-NL63 infection was associated with significant protection at 500 days (95% confidence interval [CI]: 0.05-0.54), 600 days (95% CI: 0.07-0.45), and 700 days (95% CI: 0.19-0.80), but not at earlier time points. HCoV-OC43 showed no significant association at any time point. CONCLUSIONS: Prior HCoV-NL63 infection, but not HCoV-OC43, was associated with reduced risk of symptomatic COVID-19 in children for up to 700 days. These findings provide epidemiologic support for virus-specific cross-reactive immunity and highlight pediatric-adult differences. These findings are not yet generalizable and require validation in studies using serological markers and stricter confounder control.