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Nipah virus (NiV) is an emerging highly lethal zoonotic disease that, like SARS-CoV-2, can be transmitted via respiratory droplets. Single-injection vaccines that rapidly control NiV outbreaks are needed. To assess the ability of a vaccine to induce fast-acting protection, we immunized African green monkeys with a recombinant vesicular stomatitis virus (VSV) expressing the Bangladesh strain glycoprotein (NiVBG) of NiV (rVSV-ΔGNiVBG). Monkeys were challenged 3 or 7 d later with a lethal dose of NiVB. All monkeys vaccinated with rVSV-ΔG-NiVBG 7 d prior to NiVB exposure were protected from lethal disease, while 67% of animals vaccinated 3 d before NiVB challenge survived. Vaccine protection correlated with natural killer cell and cytotoxic T cell transcriptional signatures, whereas lethality was linked to sustained interferon signaling. NiV G-specific antibodies in vaccinated survivors corroborated additional transcriptomic findings, supporting activation of humoral immunity. This study demonstrates that rVSV-based vaccines may have utility in rapidly protecting humans against NiV infection. [ABSTRACT FROM AUTHOR]