Zika virus (ZIKV) is an emerging, mosquito-transmitted flavivirus that has recently been associated with congenital malformations following infection in pregnant women, resulting in spontaneous abortion and microcephaly. The factors involved in this sudden increase in pathogenesis in humans are unclear, but may include the phenomenon of antibody-dependent enhancement (ADE). ADE is well-understood in the context of dengue virus (DENV), where prior immunity to one serotype of DENV can exacerbate a later infection by a different serotype. Because ZIKV and DENV are very closely related, and because ZIKV and DENV co-circulate in many regions including South America, it has been proposed that pre-existing immunity to DENV may be able to enhance subsequent infection with ZIKV, and that this may have been a contributing factor to the unusual severity of the recent outbreaks. We recently showed that human DENV-reactive antibodies are capable of enhancing ZIKV infection in vitro and in mice, and we now hypothesize that such antibodies can exacerbate ZIKV-mediated damage to the fetus.

We established a model to examine the effect of pre-existing immunity in the context of pregnancy by passively transferring DENV-reactive or flavivirus-naïve (control) antibodies into pregnant Stat2-/- mice prior to infection with ZIKV. We observed significantly enhanced fetal resorption and growth restriction in mice infected in the presence of DENV-reactive antibodies relative to mice infected in the presence of control antibodies, together with increased viral load, inflammation, and structural damage in the placenta (Chapter 2). We were able to confirm our findings in mice by developing a model using human placental tissue explants, and found that in both mouse and human placentas, the enhanced replication in the presence of DENV antibodies correlated with an increase in the proportion of infected trophoblasts (Chapter 3). Finally, we evaluated the enhancement potential of antibodies raised against less closely related flaviviruses, such as West Nile virus (WNV), yellow fever virus (YFV), and Japanese encephalitis virus (JEV), and found that WNV-reactive antibodies are only mildly enhancing, and the more distantly-related viruses even less so (Chapter 4). Together, these findings demonstrate that pre-existing immunity to DENV may be a risk factor for ZIKV infection and begin to shed light on the possible mechanisms behind enhancement of ZIKV in the context of pregnancy, which will have important implications for flavivirus vaccine design as well as efforts to identify and protect the most at-risk populations in future outbreaks.