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

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.