Recombinant vesicular stomatitis virus vector vaccines for WHO blueprint priority pathogens

Fathi, Anahita; Dahlke, Christine; Addo, Marylyn M.

VSV-EBOV is derived from a chimeric VSV Indiana strain, in which VSV G is replaced by the transmembrane GP of Ebola virus (formerly Zaire ebolavirus (ZEBOV), now designated EBOV), 20 derived from the Kikwit strain. VSV-EBOV was first described by a group led by Heinz Feldmann and Ute Stroeher at the National Microbiology Laboratory of Canada's Public Health agency. While the objective of the study was to assess EBOV GP pathogenicity in mice using VSV as a vector to express EBOV GP, the researchers found that inoculated mice did not develop EVD, and did, in fact, not show any symptoms after challenge with a mouse-adapted EBOV strain. 17, 23 In a following non-human primate (NHP) study, vaccinated animals were completely protected from homologous challenge, 24 and subsequent studies in NHPs provided further evidence for the tolerability and efficacy of the vaccine, administered via several routes of administrationorally, intranasally or intramuscularly, and also when receiving a high-dose aerosol EBOV challenge. 25, 26 Furthermore, in mice, even doses of as low as two plaque-forming units resulted in protection. 27 To date, VSV-EBOV has been described to be immunogenic and to elicit high titers of binding and neutralizing antibodies over a wide dose range in small and large animal models as well as in humans (reviewed in Monath et al.) . 16 In 2016, the results of phase I clinical trials generated by the VEBCON (VSV-EBOV consortium with four independent, yet harmonized investigator-initiated trials in Switzerland, Germany, Gabon and Kenya) provided a first safety and immunogenicity assessment of VSV-EBOV in humans. 28 Results of four more phase I trials in the United States and Canada were reported simultaneously (Regules et al., NEJM 2016) or shortly thereafter. [29] [30] [31] To date, a total of 17 phase I-III clinical trials have been completed or are ongoing (summarized in Tables 1 and 2) . 16, 32 VSV-EBOV is furthermore the only vaccine that is being deployed during the 10 th EBOV outbreak in the Democratic Republic of the Congo (DRC). This outbreak now constitutes the worst EBOV outbreak in the history of the country and the secondworst outbreak globally, and has consequently been recognized as a PHEIC on July 17 th , 2019. The recent developments emphasize the importance of a detailed evaluation of the ample pre-clinical, clinical and field data on VSV-EBOV gathered to date in order to ultimately expedite licensure and facilitate vaccine supply.