Prior dengue immunity enhances Zika virus infection of the maternal-fetal interface in rhesus macaques

Abstract

Concerns have arisen that pre-existing immunity to dengue virus (DENV) could enhance Zika virus (ZIKV) disease, due to the homology between ZIKV and DENV and the observation of antibody-dependent enhancement (ADE) among DENV serotypes. To date, no study has examined the impact of pre-existing DENV immunity on ZIKV pathogenesis during pregnancy in a translational non-human primate model. Here we show that prior DENV-2 exposure enhanced ZIKV infection of maternal-fetal interface tissues in macaques. However, pre-existing DENV immunity had no detectable impact on ZIKV replication kinetics in maternal plasma, and all pregnancies progressed to term without adverse outcomes or gross fetal abnormalities detectable at delivery. Understanding the risks of ADE to pregnant women worldwide is critical as vaccines against DENV and ZIKV are developed and licensed and as DENV and ZIKV continue to circulate.

Neonatal Development in Prenatally Zika Virus-Exposed Infant Macaques with Dengue Immunity

“…All dams were part of the Specific Pathogen Free (SPF) colony at the Wisconsin National Primate Research Center (WNPRC) and were free of Macacine herpesvirus 1 (Herpes B), simian retrovirus type D (SRV), simian T-lymphotropic virus type 1 (STLV), and simian immunodeficiency virus (SIV). The pregnancies of the 8 DENV/ZIKV and 4 of 5 ZIKV pregnancies have been described earlier [ 19 ]. All infant studies, along with the pregnancies of all control dams and ZIKV dam 044-109, are presented for the first time in this report.…”

“…Prior to pregnancy, eight macaques were inoculated with 1 × 10 4 PFU DENV-2/US/BID-V594/2006 37–68 days prior to breeding ( Table 1 ), as previously described [ 19 ]. Macaques were bred and, once pregnant, were inoculated subcutaneously with PBS or 1 × 10 4 PFU Zika virus/ H.sapiens-tc/PUR/2015/PRVABC59_v3c2 (PRVABC59, GenBank: KU501215) over the cranial dorsum.…”

Human immune globulin treatment controls Zika viremia in pregnant rhesus macaques

“…The other four animals were treated with 50mg/kg of HIG from ZIKV-naive individuals (placebo-IG) ( Fig 1B ). Historical, mock-infected (n = 6) and untreated (n = 9) pregnant macaques infected with the same strain, dose, and route of ZIKV were used as additional control groups for various analyses [ 22 , 23 ] ( Fig 1A ). Pregnant animals receiving ZIKV-IG or placebo-IG were monitored throughout pregnancy and a cesarean section was performed at GD155 (+/- 4 days) ( Fig 1B ).…”