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 6

VSV-EBOV vaccination does not increase placental proinflammatory cytokine levels in IFN-β–deficient dams.

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VSV-EBOV vaccination does not increase placental proinflammatory cytokin...
Pregnant C57BL/6 Ifnb1–/– mice were challenged with 105 TCID50 VSV-EBOV at E7 and sacrificed at 5 dpc (IFN-β–/– E7 Vac). Unvaccinated IFN-β–/– control dams were sacrificed at E12 (IFN-β–/– No Vac). (A) H&E staining of E12 placental sections from unvaccinated (IFN-β–/– No Vac) and vaccinated IFN-β–/– dams (IFN-β–/– E7 Vac). Scale bars: 500 μm. Quantification shows the relative proportion of placental labyrinth (PL) depth to combined PL and decidua basalis (DB) depth (left), and junctional zone (JZ) to combined JZ and labyrinth (Lab) depth (right). (B) PAS staining of E12 placental sections to assess glycogen-rich cells. Arrowheads indicate glycogen cells (GCs). Scale bars: 100 μm. The graph shows the proportion of PAS+ cells (GCs) within the JZ. (C) Masson-Goldner trichrome staining of E12 placental sections to assess SpA remodeling. Black asterisks indicate SpA. Scale bars: 100 μm. The graph shows the ratio of SpA area to luminal area. (D) DBA/PAS staining of E12 placental sections showing accumulation of mature uNK cells. Double-positive (DBA+PAS+) tissue-associated uNK (ta-uNK; left) and vascular-associated uNK (va-uNK; right) cells. Scale bars: 50 μm. Data in A–D are presented as mean ± SD (n = 4–10 per group). (E) Levels of TNF-α, IL-2, IL-6, IL-18, IL-10, IL-17A, IL-22, IL-23, IL-27, and GM-CSF were measured in placental lysates from unvaccinated (IFN-β–/– No Vac) and vaccinated IFN-β–/– dams (IFN-β–/– E7 Vac) at 5 dpc using Luminex multiplex analysis. (F) Fetal developmental stage at E12 assessed by Theiler staging (TS), presented as pie charts. Number of fetuses per group is indicated within each segment. Data are shown as mean ± SD. *P < 0.05 vs. unvaccinated IFN-β–/– controls, as determined by 2-tailed Mann-Whitney U test.