Zika Virus Infection in Pregnancy: Advanced Diagnostic Approaches in Dengue-Naive and Dengue-Experienced Pregnant Women and Possible Implication for Cross-Reactivity and Cross-Protection

Abstract

Zika virus (ZIKV) infection has been linked to congenital defects in fetuses and infants, as exemplified by the microcephaly epidemic in Brazil. Given the overlapping presence of Dengue virus (DENV) in the majority of ZIKV epidemic regions, advanced diagnostic approaches need to be evaluated to establish the role of pre-existing DENV immunity in ZIKV infection. From 2015 to 2017, five pregnant women with suspected ZIKV infection were investigated in Pavia, Italy. Among the five pregnant women, three were DENV-ZIKV immunologically cross-reactive, and two were DENV-naïve. Advanced diagnosis included the following: (i) NS1 blockade-of-binding (BOB) ELISA assay for ZIKV specific antibodies and (ii) ELISpot assay for the quantification of effector memory T cells for DENV and ZIKV. These novel assays allowed to distinguish between related flavivirus infections. The three DENV-experienced mothers did not transmit ZIKV to the fetus, while the two DENV-naive mothers transmitted ZIKV to the fetus. Pre-existing immunity in DENV experienced mothers might play a role in cross-protection.showed evidence of tissue destruction-calcifications, gliosis, and necrosis [2]. Although transmission of ZIKV has declined in the Americas, outbreaks and infection clusters continue to occur in some regions, such as India and South-east Asia, where there are large populations of women of childbearing age who are susceptible to the virus [3].Modeling of data from French Polynesia suggests about a 1% risk of microcephaly associated with maternal Zika virus infection in the first-trimester pregnancy, while a model based on data from a Zika outbreak in Bahia, Brazil, suggests a risk between 1% and 13% [4,5]. In U.S. territories (all U.S. states, the District of Columbia, and all U.S. territories except Puerto Rico), among women with timing of possible Zika infection exclusively during the first trimester, 11% had a fetus or infant with a birth defect [2]. Overall, in Brazil, a rate of 1.98 microcephaly cases per 10,000 live births per year was observed, representing an approximately nine-fold increase over the average prevalence during the previous 14 years [6,7]. In comparison, Colombia reported a smaller relative increase (four-fold), but the prevalence of reported microcephaly was approximately 9.6 per 10,000 live births [8], and in the USA, it was 8.8 per 10,000 live births [9]. There are several possible reasons for the differences in the microcephaly increase rate in the context of the ZIKV outbreaks in these countries. First, 50-75% of the population of Colombia resides at altitudes above 2000 m, in areas without mosquito vector (Aedes genus) circulation. On the other hand, the population at risk in the United States, although large, has significantly less exposure to the closely-related Dengue virus (DENV) than the Brazilian population affected by the Zika virus. This may have implications for the risk of fetal infection and disease [10,11]. ZIKV infection has been linked to congenital abnormalities in both women living in endemic countri...

Effective control of early Zika virus replication by Dengue immunity is associated to the length of time between the 2 infections but not mediated by antibodies

“…From our results we cannot anticipate if the effect of previous DENV immunity or the time between DENV and ZIKV infections may have any implications during pregnancy. However, studies addressing the role of DENV Abs in pregnant women infected with ZIKV, one from Italy and one from Brazil, concluded that preexistence of DENV Abs are not related to an increase of fetal damage [73,74]. Moreover, the Brazilian study concluded that multitypic DENV infections may protect, rather than enhance, from development of CZS.…”

Dengue and Zika Viruses: Epidemiological History, Potential Therapies, and Promising Vaccines

“…In line with that, another study with pregnant women with possible ZIKV infection found three women who were DENV and ZIKV immunologically cross-reactive and another two women who were not [179]. The three women that were previously exposed to DENV did not vertically transmit ZIKV to the fetus, while the two (who were not exposed to DENV before) did transmit the virus vertically [179]. Once more, this suggests that previous contact with DENV confers cross-protection [179].…”

“…DENV seroprevalence was significantly lower among ZIKV-seropositive mothers of children with congenital Zika syndrome (compared to ZIKV-seropositive control mothers), suggesting that DENV infection may even protect against the development of that syndrome [181]. In line with that, another study with pregnant women with possible ZIKV infection found three women who were DENV and ZIKV immunologically cross-reactive and another two women who were not [179]. The three women that were previously exposed to DENV did not vertically transmit ZIKV to the fetus, while the two (who were not exposed to DENV before) did transmit the virus vertically [179].…”

“…ZIKV and DENV are antigenically related viruses, co-circulating in certain regions [ 176 , 177 , 178 , 179 ]. One consequence of this similarity is misdiagnosis, as cross-reactivity occurs within members of this genus.…”

“…The three women that were previously exposed to DENV did not vertically transmit ZIKV to the fetus, while the two (who were not exposed to DENV before) did transmit the virus vertically [ 179 ]. Once more, this suggests that previous contact with DENV confers cross-protection [ 179 ]. At an immunological level, DENV/ZIKV cross-reactive Th1 CD4+ T cells are able to suppress ZIKV replication in an antibody-independent manner [ 182 ].…”