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

PLoS Negl Trop Dis. 2019 Mar 11;13(3):e0007246. doi: 10.1371/journal.pntd.0007246. eCollection 2019 Mar.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Antibodies, Neutralizing / blood*
  • Antibodies, Viral / blood*
  • Brazil / epidemiology
  • Case-Control Studies
  • Dengue / diagnosis*
  • Dengue / epidemiology
  • Dengue Virus / immunology
  • Female
  • Humans
  • Immunoglobulin G / blood
  • Immunoglobulin M / blood
  • Infant, Newborn
  • Male
  • Microcephaly / epidemiology*
  • Microcephaly / etiology*
  • Pregnancy
  • Pregnancy Complications, Infectious / diagnosis*
  • Pregnancy Complications, Infectious / epidemiology
  • Young Adult
  • Zika Virus / immunology
  • Zika Virus Infection / complications
  • Zika Virus Infection / diagnosis*
  • Zika Virus Infection / epidemiology

Substances

  • Antibodies, Neutralizing
  • Antibodies, Viral
  • Immunoglobulin G
  • Immunoglobulin M

Grants and funding

This study was funded by the Brazilian Ministry of Health, Pan American Health Organization, Enhancing Research Activity in Epidemic Situations. Some of the investigators received partial support from the National Advisory Board of Scientific and Technological Development (Conselho Nacional de Desenvolvimento Cientifico e Tecnologico [CNPq]; scholarship 306708/2014-0 to CMTM, 308818/2013-0 to RAAX, 308590/2013-9 to DBM-F, 308491/2013-0 to MFPMA, 304174/2014-9 to CB, and 306222/2013-2 to WVS). LCR is partly funded by the European Union’s Horizon 2020 research and innovation programme under Zika-PLAN (grant agreement no. 734584). The study also received parcial support from CuraZika to ETAM. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.