Prior dengue virus infection and risk of Zika: A pediatric cohort in Nicaragua

Abstract

Background

Zika virus (ZIKV) emerged in northeast Brazil in 2015 and spread rapidly across the Americas, in populations that have been largely exposed to dengue virus (DENV). The impact of prior DENV infection on ZIKV infection outcome remains unclear. To study this potential impact, we analyzed the large 2016 Zika epidemic in Managua, Nicaragua, in a pediatric cohort with well-characterized DENV infection histories.

Methods and findings

Symptomatic ZIKV infections (Zika cases) were identified by real-time reverse transcription PCR and serology in a community-based cohort study that follows approximately 3,700 children aged 2–14 years old. Annual blood samples were used to identify clinically inapparent ZIKV infections using a novel, well-characterized serological assay. Multivariable Poisson regression was used to examine the relation between prior DENV infection and incidence of symptomatic and inapparent ZIKV infection. The generalized-growth method was used to estimate the effective reproduction number. From January 1, 2016, to February 28, 2017, 560 symptomatic ZIKV infections and 1,356 total ZIKV infections (symptomatic and inapparent) were identified, for an overall incidence of 14.0 symptomatic infections (95% CI: 12.9, 15.2) and 36.5 total infections (95% CI: 34.7, 38.6) per 100 person-years. Effective reproduction number estimates ranged from 3.3 to 3.4, depending on the ascending wave period. Incidence of symptomatic and total ZIKV infections was higher in females and older children. Analysis of the effect of prior DENV infection was performed on 3,027 participants with documented DENV infection histories, of which 743 (24.5%) had experienced at least 1 prior DENV infection during cohort follow-up. Prior DENV infection was inversely associated with risk of symptomatic ZIKV infection in the total cohort population (incidence rate ratio [IRR]: 0.63; 95% CI: 0.48, 0.81; p < 0.005) and with risk of symptomatic presentation given ZIKV infection (IRR: 0.62; 95% CI: 0.44, 0.86) when adjusted for age, sex, and recent DENV infection (1–2 years before ZIKV infection). Recent DENV infection was significantly associated with decreased risk of symptomatic ZIKV infection when adjusted for age and sex, but not when adjusted for prior DENV infection. Prior or recent DENV infection did not affect the rate of total ZIKV infections. Our findings are limited to a pediatric population and constrained by the epidemiology of the site.

Conclusions

These findings support that prior DENV infection may protect individuals from symptomatic Zika. More research is needed to address the possible immunological mechanism(s) of cross-protection between ZIKV and DENV and whether DENV immunity also modulates other ZIKV infection outcomes such as neurological or congenital syndromes.

Abstract

Eva Harris and colleagues reveal the protective effect of previous dengue virus infection against symptomatic Zika in a large pediatric cohort in Nicaragua during the 2016 Zika epidemic

Author summary

Why was this study done?

• Zika virus (ZIKV) was introduced into the Americas—a region with high levels of dengue virus (DENV) immunity—in 2015.

• Immunity generated by infection with one DENV serotype impacts the outcomes of subsequent infection with a different DENV serotype.

• Because ZIKV and DENV are closely related flaviviruses, it is possible that pre-existing DENV immunity may also impact susceptibility to Zika.

What did the researchers do and find?

• In 2016, we followed the introduction and spread of ZIKV in a large, long-term cohort of children in Managua, Nicaragua, to determine who was infected with ZIKV and, of those, who developed symptomatic infection. For most of these children, the history of prior DENV infection had been well characterized.

• We found that children with prior DENV infection had lower rates of symptomatic Zika than children who did not have prior DENV infection.

• However, we found that prior DENV immunity did not affect the overall rate of ZIKV infection in children.

What do these findings mean?

• These findings support the idea that prior DENV immunity might cross-protect against symptomatic Zika.

• Future studies are required to address the immunological mechanisms of cross-protection observed, as well as to examine whether prior DENV immunity impacts severe ZIKV infection outcomes such as neurological or congenital syndromes.