Abstract: Zika infection during pregnancy is associated with fetal death and microcephaly. There is a desperate need for a maternal vaccine that can protect pregnant women and their babies from Zika. While rodents and other small animal models are suitable for many aspects of vaccine research, when it comes to vaccination during pregnancy, rabbits are the small animal model that accurately models the transfer of maternal antibodies developed after vaccination to offspring. Thus, the rabbit could be the only small animal model that can simultaneously test safety, efficacy, and immunogenicity of maternal vaccines. While a 1950s study showed that Zika is immunogenic in rabbits, the effects of Zika infection during pregnancy is not yet known. Our goal is to characterize Zika infection in pregnant rabbits and determine if infection results in fetal pathology. We hypothesize that pregnant rabbits are susceptible to Zika infection, and resulting fetal infection induces neurologic deficits and pathology. In Aim 1, we will determine if pregnant rabbits are susceptible to Zika infection when Zika is administered by a variety of routes that may model natural transmission of Zika in humans. Intravenous challenge will be used as a control, with intradermal challenge modelling mosquito transmission, intravaginal challenge modelling sexual transmission to women, and oral challenge modelling transmission by kissing or oral sex. We will determine if the virus is present in the mother's blood, urine, saliva, or breast milk and will also determine if the pregnant rabbit develops an antibody response to Zika. In Aim 2, we will follow the babies born to the Zika infected rabbits in Aim 1 to characterize fetal pathology after Zika exposure in utero. To determine if there is active infection of fetuses with Zika virus after exposure during pregnancy, we will determine if there is detectable viral RNA in stillborn or aborted fetuses and we will test placentas from live born offspring. We will then study the development of offspring to determine if there are any developmental deficits. All offspring will have a complete physical, neurologic, and histopathologic exam at 4-6 weeks of age to determine if there are neurologic defects or other Zika- associated pathology. This aim will allow us to characterize fetal associated pathology after maternal exposure to Zika virus in rabbits. Rabbits are an ideal model for maternal vaccine development as they are one of only few species that models maternal: fetal immunology in humans. This grant will investigate their ability to model Zika infection in pregnant women and the resulting fetal pathology observed during the ongoing pandemic. Such knowledge would be very useful for elucidating the role of the rabbit in Zika pathogenesis research, and in the research and development of a maternal Zika vaccine to prevent the tragic effects of fetal exposure to Zika virus.