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Abstract

Since the West African Ebola virus (EBOV) epidemic in 2014-2016, recurrent outbreaks of the EBOV-Makona variant have been driven by recrudescence and human-to-human transmission emphasizing the need for effective vaccination strategies. A live-attenuated recombinant vesicular stomatitis virus (VSV)-based vaccine expressing the EBOV-Kikwit variant glycoprotein (VSV-Kik) received FDA approval in December 2019 and provides complete, rapid protection against EBOV-Makona as early as 7 days post-vaccination (DPV). During the 2018-2020 Ebola outbreak, the VSV-Kik vaccine, known as ERVEBO, was administered to lower-risk individuals at a 5-fold dose reduction of the standard 2 × 10 7 PFU to provide broader population protection. Identification of a protective lower dose providing rapid protection would ease supply burdens during future outbreaks and enhance vaccine coverage. We previously generated a VSV-based vaccine expressing the glycoprotein of the Makona variant (VSV-Mak) which provided complete protection against homologous challenge 28 DPV at as low as 1 × 10 1 PFU. However, the transcriptional responses engendered by VSV-Mak and VSV-Kik vaccines in the context of early EBOV-Makona challenge have not yet been evaluated. In the current study, we compared transcriptional responses following a low dose (1 × 10 4 PFU) of lab-grade VSV-Mak or GMP-grade VSV-Kik and subsequent EBOV-Makona challenge 10 DPV. VSV-Kik provided complete protection against heterologous challenge and elicited rapid antiviral transcriptional changes followed by the activation of adaptive immunity. On the other hand, VSV-Mak only provided partial protection and induced minimal transcriptional response. These results highlight a glycoprotein-specific transcriptional response after vaccination despite the high EBOV variant homology.

Document Type

Article

Publication Date

2026

Notes/Citation Information

0264-410X/© 2026 Elsevier Ltd. All rights are reserved, including those for text and data mining, AI training, and similar technologies.

Digital Object Identifier (DOI)

https://doi.org/10.1016/j.vaccine.2026.128410

Funding Information

This study was supported by intramural funding from the National Institutes of Health and the University of Kentucky. These funding sources had no involvement in study design; collection, analysis, and interpretation of data; writing of the report; or the decision to submit the article for publication.

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