Abstract
The potential risk of yellow fever (YF) infection in unvaccinated pregnant women has aroused serious concerns. In this study, we evaluated the effect of the YF vaccine during gestation using a mouse model, analyzing placental structure, immunolocalization of the virus antigen, and viral activity at the maternal-fetal barrier and in the maternal liver and fetus. The YF vaccine (17DD) was administered subcutaneously at a dose of 2.0 log10 PFU to CD-1 mice on gestational days (gd) 0.5, 5.5, and 11.5 (n = 5–10/group). The control group received sterile saline (n = 5–10/group). Maternal liver, implantation sites with fetus, and placentas were collected on gd18.5. The numbers of implantation sites, reabsorbed embryos, and stillborn fetuses were counted, and placentas and live fetuses were weighed. Tissues (placenta, fetuses, and liver) of vaccinated pregnant mice on gd5.5 (n = 15) were paraffin-embedded in 10% buffered-formalin and collected in TRIzol for immunolocalization of YF vaccine virus and PCR, respectively. PCR products were also subjected to automated sequence analysis. Fetal growth restriction (p < 0.0001) and a significant decrease in fetal viability (p < 0.0001) occurred only when the vaccine was administered on gd5.5. In stillbirths, the viral antigen was consistently immunolocalized at the maternal-fetal barrier and in fetal organs, suggesting a transplacental transfer. In stillbirths, RNA of the vaccine virus was also detected by reverse transcriptase-PCR indicating viral activity in the maternal liver and fetal tissues. In conclusion, the findings of this study in the mouse suggest that vaccination did not cause adverse outcomes with respect to fetal development except when administered during the early gestational stage, indicating the implantation period as a susceptible period in which the YF vaccine virus might interfere with pregnancy.
Highlights
Yellow fever (YF) is an acute viral infection associated with hepatitis, jaundice, hemorrhage, and renal failure, and it may progress to death (Monath, 2008; Staples and Monath, 2011)
In 2017, yellow fever (YF) virus (YFV) was detected in non-human primates, and human cases were reported in places where vaccination coverage was low (Leal et al, 2016; Fernandes et al, 2017), a situation that may have been aggravated by public hesitancy toward vaccines
This study addressed the birth/mortality rates, as well as the morphology and localization of YF 17D virus in fetuses, placentas, and maternal tissues after vaccination through immunohistochemical reactions and polymerase chain reaction (PCR)
Summary
Yellow fever (YF) is an acute viral infection associated with hepatitis, jaundice, hemorrhage, and renal failure, and it may progress to death (Monath, 2008; Staples and Monath, 2011). The virus infects the Kupffer cells and the hepatocytes, causing severe necrosis (Monath and Barrett, 2003). The YF 17D vaccine causes a transient low viremia (Monath and Barrett, 2003) accompanied by innate immune responses with detectable levels of cytokines and toll-like receptor-mediated signaling (Monath and Vasconcelos, 2015). A small number of adverse events have been associated with vaccination in humans and monkeys, ranging from severe encephalitis and hepatic failure to neurological symptoms of benign prognosis (Monath and Barrett, 2003; Martins et al, 2015). Recent studies suggest that maternal immunity, time of gestation, coinfections, and many other factors may be associated with this effectiveness (Marinho et al, 2017). This study addressed the birth/mortality rates, as well as the morphology and localization of YF 17D virus in fetuses, placentas, and maternal tissues after vaccination through immunohistochemical reactions and polymerase chain reaction (PCR)
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