Congenital abnormalities associated with Zika virus infection–Dengue as potential co-factor? A systematic review

Abstract

Zika virus (ZIKV) emerged in Brazil during 2013–2014 causing an epidemic of previously unknown congenital abnormalities. The frequency of severe congenital abnormalities after maternal ZIKV infection revealed an unexplained geographic variability, especially between the Northeast and the rest of Brazil. Several reasons for this variability have been discussed. Prior immunity against Dengue virus (DENV) affecting ZIKV seems to be the most likely explanation. Here we summarise the current evidence regarding this prominent co-factor to potentially explain the geographic variability. This systematic review followed the PRISMA guidelines. The search was conducted up to May 15th, 2020, focussing on immunological interactions from Zika virus with previous Dengue virus infections as potential teratogenic effect for the foetus. Eight out of 339 screened studies reported on the association between ZIKV, prior DENV infection and microcephaly, mostly focusing on antibody-dependent enhancement (ADE) as potential pathomechanism. Prior DENV infection was associated with enhancement for ZIKV infection and increased neurovirulence in one included in vitro study only. Interestingly, the seven in vivo studies exhibited a heterogeneous picture with three studies showing a protective effect of prior DENV infections and others no effect at all. According to several studies, socio-economic factors are associated with increased risk for microcephaly. Very few studies addressed the question of unexplained variability of infection-related microcephaly. Many studies focussed on ADE as mechanism without measuring microcephaly as endpoint. Interestingly, three of the included studies reported a protective effect of prior DENV infection against microcephaly. This systematic review strengthens the hypothesis that immune priming after recent DENV infection is the crucial factor for determining protection or enhancement activity. It is of high importance that the currently ongoing prospective studies include a harmonised assessment of the potential candidate co-factors.

Nonhuman Primate Models of Zika Virus Infection and Disease during Pregnancy

“…ADE, in which virus uptake and infection are increased via the interaction of cellular Fcγ receptors with an antibody-bound (but not neutralized) virus, has been most prominently demonstrated during sequential infection with heterologous serotypes of dengue virus [ 79 ]. ADE of ZIKV infection has also been demonstrated with anti-DENV antibodies in vitro and in mice [ 80 ], although not in NHPs or humans [ 81 , 82 , 83 , 84 , 85 ]. However, the ability of maternal antibodies to enhance ZIKV infection in culture demonstrated a positive correlation between enhancement titers and adverse pregnancy outcomes in humans and NHPs [ 86 ], suggesting that placental FcRn receptors may mediate increased uptake of the virus.…”

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

“…In non-pregnant macaque studies, the presence of DENV IgG does not increase ZIKV titers or disease [ 7 , 8 ]. Human pregnancy studies have begun teasing apart this question by examining pregnancies with prenatal ZIKV exposure and DENV immunity, and defining rates of miscarriage, abnormal infant physical exams, congenital Zika syndrome, and abnormal infant neuroimaging [ 9 ]. The role of maternal DENV immunity on prenatal ZIKV infection varies between the populations studied, with some studies identifying no change in the rates of miscarriage and microcephy [ 10 , 11 , 12 ], and others finding that maternal DENV immunity may reduce the risk of congenital Zika syndrome [ 13 ].…”

Contributions of Genetic Evolution to Zika Virus Emergence

“…Early in vitro and mouse studies reported that preexisting anti-DENV immunity associated with ZIKV pathogenesis via antibody-dependent enhancement (ADE) (Stettler et al, 2016;Bardina et al, 2017;Rathore et al, 2019); however, clinical and epidemiological evidence for ADE has not been provided yet. In contrast, human studies demonstrated that previous DENV immunity had no or cross-protection impact against ZIKV infection (Halai et al, 2017;Moreira-Soto et al, 2017;Castanha et al, 2019;Pedroso et al, 2019;Katzelnick et al, 2020;Michlmayr et al, 2020;Tonnerre et al, 2020;Petzold et al, 2021). In the Nicaraguan and Brazil pediatric cohorts, prior DENV infection and pre-existing anti-NS1 DENV antibodies were associated with reduced risk of ZIKV infection and disease (Gordon et al, 2019;Rodriguez-Barraquer et al, 2019).…”