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Protective Association of Endemic HCoV-NL63 With Symptomatic COVID-19 in a Pediatric Cohort
Fujio Kakuya1, Yutaka Saisho2,3, Ryuta Terao1
1From the Department of Pediatrics, Furano Kyokai Hospital, Furano, Japan.
Insights
Prior infection with human coronavirus NL63 (HCoV-NL63) protected children against symptomatic COVID-19 for up to 700 days. This provides evidence for cross-immunity, explaining why children have milder COVID-19 than adults.
Area of Science:
- Pediatric infectious diseases
- Epidemiology of viral respiratory infections
- Immunology of cross-reactivity
Background:
- Children generally experience less severe COVID-19 than adults, possibly due to prior immunity from endemic human coronaviruses (HCoVs).
- Longitudinal epidemiologic data supporting this cross-immunity in children is limited.
- Outbreaks of HCoV-NL63 and HCoV-OC43 provided an opportunity to study this phenomenon in Japan.
Purpose of the Study:
- To investigate the longitudinal association between prior endemic human coronavirus (HCoV) infections and the risk of symptomatic COVID-19 in children.
- To compare the protective effects of HCoV-NL63 and HCoV-OC43 against COVID-19 in a pediatric cohort.
Main Methods:
- A prospective longitudinal cohort study involving 237 children followed for up to 700 days.
- Comparison of children with HCoV-NL63 or HCoV-OC43 infections against those infected with other respiratory viruses.
- Statistical analyses included Kaplan-Meier estimation, log-rank tests, and multivariate Cox regression to assess time to symptomatic COVID-19.
Main Results:
- Children with prior HCoV-NL63 infection showed a significantly reduced cumulative incidence of symptomatic COVID-19 through 700 days (P = 0.03).
- Multivariable analysis confirmed HCoV-NL63 infection was associated with significant protection at 500, 600, and 700 days post-infection.
- No significant protective effect against symptomatic COVID-19 was observed for prior HCoV-OC43 infection at any time point.
Conclusions:
- Prior HCoV-NL63 infection, but not HCoV-OC43, is linked to a decreased risk of symptomatic COVID-19 in children over a 700-day period.
- These findings offer epidemiologic support for virus-specific cross-reactive immunity contributing to milder COVID-19 in children.
- Further validation using serological markers and improved confounder control is needed for generalizability.
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.
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