Rift Valley Fever Vaccine Virus Clone 13 Is Able to Cross the Ovine Placental Barrier Associated with Foetal Infections, Malformations, and Stillbirths

Makoschey, B.; Kilsdonk, Emma van; Hubers, Willem R.; Vrijenhoek, Mieke P.; Smit, Marianne; Schreur, Paul J. Wichgers; Kortekaas, Jeroen; Moulin, Véronique

doi:10.1371/journal.pntd.0004550

Cited by 55 publications

(46 citation statements)

References 29 publications

(29 reference statements)

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“…We therefore hypothesize that RVFV NSs facilitates replication in placental tissues by downregulating JAK/STAT signalling. On the other hand, previous studies have demonstrated that RVFV can also cross the ovine placental barrier without NSs [35]. These infections did not result in abortions but instead in stillbirths and congenital malformations, including arthrogryposis and hydranencephaly, resembling pathology in ovine foetuses infected by members of the genus Orthobunyavirus, such as Schmallenberg virus.…”

Section: Discussionmentioning

confidence: 87%

Rift Valley fever virus targets the maternal-foetal interface in ovine and human placentas

et al. 2020

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Background Rift Valley fever virus (RVFV) is an arbovirus of the order Bunyavirales that causes severe disease in ruminants and humans. Outbreaks in sheep herds are characterised by newborn fatalities and abortion storms. The association of RVFV infections with abortions of ovines and other ruminants is well recognized, whereas the pathology resulting in abortion has remained undescribed. Accumulating evidence suggests that RVFV is abortogenic in humans as well, warranting more research on the interaction of RVFV with the ruminant and human placenta. Methodology/Principal findings Pregnant ewes were inoculated with a highly virulent strain of RVFV and necropsied at different days post infection. Tissues were collected and analysed by PCR, virus isolation, and immunohistochemistry. The results show that RVFV replicates efficiently in maternal placental epithelial cells before the virus infects foetal trophoblasts. Moreover, the virus was shown to bypass the maternal epithelial cell layer by directly targeting foetal trophoblasts in the haemophagous zone, a region of the ovine placenta where maternal blood is in direct contact with foetal cells. Abortion was associated with widespread necrosis of placental tissues accompanied with severe haemorrhages. Experiments with human placental explants revealed that the same virus strain replicates efficiently in both cyto-and syncytiotrophoblasts. Conclusions/Significance This study demonstrates that RVFV targets the foetal-maternal interface in both ovine and human placentas. The virus was shown to cross the ovine placental barrier via two distinct routes, ultimately resulting in placental and foetal demise followed by abortion. Our finding that RVFV replicates efficiently in human trophoblasts underscores the risk of RVFV infection for human pregnancy.

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Section: Discussionmentioning

confidence: 87%

Rift Valley fever virus targets the maternal-foetal interface in ovine and human placentas

et al. 2020

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“…The recently developed Clone 13 vaccine, which lacks 69% of the non-structural protein S (NSs) gene, also possesses a risk of vertical transmission of the virus into the fetus [43]. Ewes at 50 days of pregnancy were vaccinated with an overdose of Clone 13 vaccine (6.8 log 10 TCID 50 , s.c.) to evaluate the vaccine’s safety.…”

Section: Adverse Effects Of Rvf Vaccination In Pregnant Animalsmentioning

confidence: 99%

Rift Valley fever vaccines: an overview of the safety and efficacy of the live-attenuated MP-12 vaccine candidate

Ikegami

2017

Expert Review of Vaccines

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Introduction Rift Valley fever (RVF) is a mosquito-borne zoonotic viral disease endemic to Africa and the Arabian Peninsula. High rates of abortion among infected ruminants and hemorrhagic fever in infected humans are major public health concerns. Commercially available veterinary RVF vaccines are important for preventing the spread of the Rift Valley fever virus (RVFV) in endemic countries; however, RVFV outbreaks continue to occur frequently in endemic countries in the 21st century. In the U.S., the live-attenuated MP-12 vaccine has been developed for both animal and human vaccination. This vaccine strain is well attenuated, and a single dose induces neutralizing antibodies in both ruminants and humans. Areas covered This review describes scientific evidences of MP-12 vaccine efficacy and safety, as well as MP-12 variants recently developed by reverse genetics, in comparison with other RVF vaccines. Expert commentary The containment of active RVF outbreaks and long-term protection from RVF exposure to infected mosquitoes are important goals for RVF vaccination. MP-12 vaccine will allow immediate vaccination of susceptible animals in case of an unexpected RVF outbreak in the U.S., whereas MP-12 vaccine may be also useful for the RVF control in endemic regions.

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“…While the abortogenic effect of RVFV in pregnant livestock is historically well-known, the mechanisms underlying these observations are not. The teratogenic potential of live-attenuated vaccine candidates are assessed in pregnant sheep, despite the lack of data on the basic mechanism of vertical transmission of wild-type virus (53, 54). Our findings here are noteworthy because this is the first time direct vertical transmission through the placenta has been demonstrated in a species other than livestock.…”

Section: Discussionmentioning

confidence: 99%

Rift Valley fever virus induces fetal demise through direct placental infection

Arora

et al. 2018

Preprint

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14Rift Valley fever virus (RVFV) infections in pregnant livestock are associated with high 15 rates of fetal demise and have been linked to miscarriage in pregnant women. To address how 16 acute RVFV infection during pregnancy causes detrimental effects on the fetus, we developed an 17 immunocompetent pregnant rodent model of RVFV infection. We found that pregnant rats were 18 more susceptible to RVFV-induced death than their non-pregnant counterparts and that RVFV 19 infection resulted in intrauterine fetal death and severe congenital abnormalities, even in pups from 20 infected asymptomatic pregnant rats. Virus distribution in infected dams was widespread, with a 21 previously unrecognized preference for infection, replication, and tissue damage in the placenta. 22In human mid-gestation placental tissue, RVFV directly infected placental chorionic villi, with 23 replication detected in the outermost syncytial layer. Our work identifies direct placental infection 24 by RVFV as a mechanism for vertical transmission and points to the teratogenic potential of this 25 virus in humans. This is the first time vertical transmission of RVFV has been shown in species 26

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Rift Valley Fever Vaccine Virus Clone 13 Is Able to Cross the Ovine Placental Barrier Associated with Foetal Infections, Malformations, and Stillbirths

Cited by 55 publications

References 29 publications

Rift Valley fever virus targets the maternal-foetal interface in ovine and human placentas

Rift Valley fever virus targets the maternal-foetal interface in ovine and human placentas

Rift Valley fever vaccines: an overview of the safety and efficacy of the live-attenuated MP-12 vaccine candidate

Rift Valley fever virus induces fetal demise through direct placental infection

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