Immunologic and placental responses to the VSV-EBOV vaccine in a pregnant mouse model
Aaron P. Lewkowicz, Yiru Wang, Mirian I. Mendoza, Kaliroi Engel, Logan Kelley-Baker, Iara Rattner, Amber Lopez, Ian L. McWilliams, Derek D.C. Ireland, Mohanraj Manangeeswaran, Ha-Na Lee, Daniela Verthelyi, Sandra M. Blois
Aaron P. Lewkowicz, Yiru Wang, Mirian I. Mendoza, Kaliroi Engel, Logan Kelley-Baker, Iara Rattner, Amber Lopez, Ian L. McWilliams, Derek D.C. Ireland, Mohanraj Manangeeswaran, Ha-Na Lee, Daniela Verthelyi, Sandra M. Blois
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Research Article Infectious disease Reproductive biology

Immunologic and placental responses to the VSV-EBOV vaccine in a pregnant mouse model

Abstract

Ebola virus disease is a severe viral hemorrhagic illness with high maternal and perinatal mortality. Although the replication-competent vesicular stomatitis virus–based Ebola vaccine (VSV-EBOV) has been deployed successfully in outbreak settings, pregnant women were excluded from clinical trials, leaving critical safety gaps. To address this, we developed a murine model to assess pregnancy outcomes following VSV-EBOV exposure at different gestational stages. Pregnant C57BL/6 mice vaccinated at embryonic day 7 (E7), E10, or E15 mounted robust anti–Ebola virus (anti-EBOV) antibody responses comparable to those of non-pregnant controls and efficiently cleared the vaccine virus without evidence of vertical transmission. However, peri-implantation vaccination modestly increased fetal resorption and early postnatal mortality, accompanied by placental pathology characterized by vascular remodeling defects and inflammation. Later gestational vaccination had minimal impact on survival or offspring development. Mechanistic studies revealed that these adverse effects were mediated by type I interferon signaling rather than direct viral infection, as IFN-β–deficient mice exhibited normal pregnancy outcomes and blocking interferon receptor activity ameliorated placental pathology despite higher viral loads. To our knowledge, these findings represent the first comprehensive preclinical safety evaluation of VSV-EBOV vaccination during pregnancy and identify a critical window of vulnerability early in gestation. More broadly, this work underscores the central role of interferons in shaping placental immune responses and provides an experimental framework to guide evaluation of live-virus vaccines in pregnancy.

Authors

Aaron P. Lewkowicz, Yiru Wang, Mirian I. Mendoza, Kaliroi Engel, Logan Kelley-Baker, Iara Rattner, Amber Lopez, Ian L. McWilliams, Derek D.C. Ireland, Mohanraj Manangeeswaran, Ha-Na Lee, Daniela Verthelyi, Sandra M. Blois

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Figure 4

Offspring born to VSV-EBOV–vaccinated dams display comparable growth and behavioral outcomes.

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Offspring born to VSV-EBOV–vaccinated dams display comparable growth and...
(A) Offspring born to unvaccinated (No Vac) dams (n = 14) or dams vaccinated at E7 (E7 Vac) (n = 30) were monitored for body weight changes over 60 days. PN, postnatal. (B–G) Female and male 6-month-old offspring born to unvaccinated (No Vac) dams or dams vaccinated at E7 (E7 Vac), E10 (E10 Vac), or E15 (E15 Vac) were assessed for body weight (B) and behavioral performance (C–G). (C) Open field test: total distance traveled, average speed, total freezing time, and time spent in the center 50% and 25% of the arena. (D and E) Elevated plus maze: total distance traveled, distance traveled in open arms, average speed, total freezing time, and time spent in open arms. (F) Novel object recognition test: interaction ratio (novel vs. familiar object), calculated as time spent with novel relative to familiar objects. (G) Rotarod test: average latency to fall (mean of 3 trials per mouse) on an accelerating rotating rod over 180 seconds. Data are shown as mean ± SD (n = 5–25 per group). *P < 0.05, **P < 0.01 vs. offspring from unvaccinated dams, as determined by 1-way ANOVA followed by Dunnett’s multiple-comparison test.