pathogens Review Vesicular Stomatitis Virus: From Agricultural Pathogen to Vaccine Vector Guodong Liu 1,† , Wenguang Cao 1,† , Abdjeleel Salawudeen 2 , Wenjun Zhu 3 , Karla Emeterio 1,2 , David Safronetz 1,2, * and Logan Banadyga 1, *   Citation: Liu, G.; Cao, W.; Salawudeen, A.; Zhu, W.; Emeterio, K.; Safronetz, D.; Banadyga, L. Vesicular Stomatitis Virus: From Agricultural Pathogen to Vaccine Vector. Pathogens 2021, 10, 1092. https://doi.org/10.3390/ pathogens10091092 Academic Editors: Anne Sally Davis and Barbara S Drolet Received: 30 July 2021 Accepted: 25 August 2021 Published: 27 August 2021 Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affil- iations. Copyright: © 2021 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/). 1 Special Pathogens Program, National Microbiology Laboratory, Public Health Agency of Canada, Winnipeg, MB R3E 3R2, Canada; guodong.liu@phac-aspc.gc.ca (G.L.); wenguang.cao@phac-aspc.gc.ca (W.C.); karla.emeterio@phac-aspc.gc.ca (K.E.) 2 Department of Medical Microbiology and Infectious Diseases, University of Manitoba, Winnipeg, MB R3E 0J9, Canada; salawuda@myumanitoba.ca 3 Canadian Food Inspection Agency, National Centre for Foreign Animal Disease, Winnipeg, MB R3E 3M4, Canada; wenjun.zhu@inspection.gc.ca * Correspondence: david.safronetz@phac-aspc.gc.ca (D.S.); logan.banadyga@phac-aspc.gc.ca (L.B.) † Guodong Liu and Wenguang Cao contributed equally to this manuscript. Abstract: Vesicular stomatitis virus (VSV), which belongs to the Vesiculovirus genus of the family Rhabdoviridae, is a well studied livestock pathogen and prototypic non-segmented, negative-sense RNA virus. Although VSV is responsible for causing economically significant outbreaks of vesicular stomatitis in cattle, horses, and swine, the virus also represents a valuable research tool for molecular biologists and virologists. Indeed, the establishment of a reverse genetics system for the recovery of infectious VSV from cDNA transformed the utility of this virus and paved the way for its use as a vaccine vector. A highly effective VSV-based vaccine against Ebola virus recently received clinical approval, and many other VSV-based vaccines have been developed, particularly for high- consequence viruses. This review seeks to provide a holistic but concise overview of VSV, covering the virus’s ascension from perennial agricultural scourge to promising medical countermeasure, with a particular focus on vaccines. Keywords: vesicular stomatitis virus; VSV; vaccine; countermeasure; Ebola virus; VSV-EBOV; reverse genetics; medical countermeasure 1. Vesicular Stomatitis Virus 1.1. The Virus and Its Replication The Vesiculovirus genus comprises a group of morphologically and genetically related viruses that infect mammals, birds, and reptiles [1]. Within this genus, the term “vesic- ular stomatitis virus” encompasses a number of related viruses belonging to a common serogroup, which is divided into the New Jersey and Indiana serotypes. The New Jer- sey serotype contains vesicular stomatitis New Jersey virus (VSNJV), while the Indiana serotype is further sub-divided into four distinct serological complexes. Indiana 1 contains vesicular stomatitis Indiana virus (VSIV), Indiana 2 contains Cocal virus (COCV), Indiana 3 contains vesicular stomatitis Alagoas virus (VSAV), and Indiana 4 contains Morreton virus (MORV). All of these VSVs, with the possible exception of MORV, are responsible for causing vesicular stomatitis disease in livestock animals in the Americas (described below), and VSIV is most commonly recognized as the type species for the genus Vesiculovirus. The abbreviation “VSV” will be used to refer, in general, to members of the VSV serogroup, with specific viruses identified as necessary. Notably, a number of other vesiculoviruses, such as Piry virus from South America, Chandipura virus from South Asia, and Isfahan virus from Western Asia, also cause disease in mammals but will not be considered in this review. Pathogens 2021, 10, 1092. https://doi.org/10.3390/pathogens10091092 https://www.mdpi.com/journal/pathogens