Perinatal analyses of Zika- and dengue virus-specific neutralizing antibodies: A microcephaly case-control study in an area of high dengue endemicity in Brazil

Abstract

Laboratory confirmation of Zika virus (ZIKV) infection during pregnancy is challenging due to cross-reactivity with dengue virus (DENV) and limited knowledge about the kinetics of anti-Zika antibody responses during pregnancy. We described ZIKV and DENV serological markers and the maternal-fetal transfer of antibodies among mothers and neonates after the ZIKV microcephaly outbreak in Northeast Brazil (2016). We included 89 microcephaly cases and 173 neonate controls at time of birth and their mothers. Microcephaly cases were defined as newborns with a particular head circumference (2 SD below the mean). Two controls without microcephaly were matched by the expected date of delivery and area of residence. We tested maternal serum for recent (ZIKV genome, IgM and IgG3 anti-NS1) and previous (ZIKV and DENV neutralizing antibodies [NAbs]) markers of infection. Multiple markers of recent or previous ZIKV and DENV infection in mothers were analyzed using principal component analysis (PCA). At delivery, 5.6% of microcephaly case mothers and 1.7% of control mothers were positive for ZIKV IgM. Positivity for ZIKV IgG3 anti-NS1 was 8.0% for case mothers and 3.5% for control mothers. ZIKV NAbs was slightly higher among mothers of cases (69.6%) than that of mothers of controls (57.2%; p = 0.054). DENV exposure was detected in 85.8% of all mothers. PCA discriminated two distinct components related to recent or previous ZIKV infection and DENV exposure. ZIKV NAbs were higher in newborns than in their corresponding mothers (p<0.001). We detected a high frequency of ZIKV exposure among mothers after the first wave of the ZIKV outbreak in Northeast Brazil. However, we found low sensitivity of the serological markers to recent infection (IgM and IgG3 anti-NS1) in perinatal samples of mothers of microcephaly cases. Since the neutralization test cannot precisely determine the time of infection, testing for ZIKV immune status should be performed as early as possible and throughout pregnancy to monitor acute Zika infection in endemic areas.

Efficient transplacental IgG transfer in women infected with Zika virus during pregnancy

“…Our study corroborates recent findings demonstrating efficient transfer of ZIKV, DENV3 and DENV4 neutralizing antibodies in mother-infant pairs from the Northeast of Brazil in 2016 [61]. Specifically, Castanha et al found that newborns with the outcome of micrcephaly, some of whom were exposed to ZIKV in utero, had no evidence of impaired transfer of neutralizing antibodies at birth as compared to controls without microcephaly [61]. Our work complements the finding from that case-control study through a prospective cohort design, in which we identified women with ZIKV infection during pregnancy and followed up until delivery to quantify impact on transplacental IgG transfer.…”

“…This phenomenon impacts antibody half-life in infant circulation and protection in early life. While prior studies show efficient transfer of recently boosted flavivirus antibodies after the ZIKV epidemic [61], we further examined whether pre-existing IgG subpopulations relevant to newborn health are efficiently transferred following maternal ZIKV infection.…”

Complex Scenario of Homotypic and Heterotypic Zika Virus Immune Enhancement

“…Whether the findings from Shim et al, whose data were raised in vitro and in experimental infections of immunodeficient mice, are clinically relevant thus remains unknown. Notably, our groups previously found that mothers of CZS cases had significantly higher, not lower, ZIKV-specific antibody titers than controls (9, 10). One the one hand, these data seem at odds with the experimental data reported by Shim et al On the other hand, antibody titrations were performed months after ZIKV infection, and maternal antibody titers in CZS cases may have been boosted by prolonged Zika viremia potentially elicited by fetal-maternal ZIKV shedding (11).…”

Early epilepsy in children with Zika‐related microcephaly in a cohort in Recife, Brazil: Characteristics, electroencephalographic findings, and treatment response

“…Zika virus (ZIKV) was identified as the teratogenic agent, and intrauterine ZIKV infections were observed to have repercussions for the formation and development of the fetal nervous system. 1,2 To address the public health emergency of congenital Zika syndrome (CZS), the Microcephaly Epidemic Research Group (MERG; http://www.cpqam.fiocr uz.br/merg/) was formed in late 2015 and subsequently initiated three epidemiological investigations: a case-control study of microcephaly, for which the results have been published, [3][4][5] a cohort study of pregnant women with rash, 6 and a cohort of children with potential prenatal exposure to ZIKV. In addition, MERG reported on a large case series of children with microcephaly 2 and proposed an initial description of CZS.…”