Recombinant vesicular stomatitis virus vector vaccines for WHO blueprint priority pathogens

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

The arenavirus LASV is one of the primary causal agents of hemorrhagic fevers worldwide with more than 300,000 estimated infections recorded annually in West Africa, where it is endemic. 100 It is a rodent-transmitted disease and, while disease courses are highly diverse depending on LASV clade, morbidity is significant. 100 Since January 2019, Nigeria has been facing an ongoing outbreak of Lassa fever with 526 confirmed cases of LASV infections and 121 deaths (casefatality rate 23%, Nigeria Center for Disease Control (NCDC) as of March 31, 2019) . 101 Due to its widespread geographic distribution, high incidence and the lack of a preventive vaccine or approved therapies, LASV has been identified as an emerging virus for which R&D efforts are given very high priority by multiple international professional organizations, including the Coalition for Epidemic Preparedness Innovations (CEPI) and WHO. 102 Analogous to rVSV vectors expressing MARV and EBOV GP, Drs. Feldmann and Stroeher had described a LASV Glycoprotein C (GPC) expressing rVSV, VSVΔG/LASVGPC (clade IV, isolate Josiah), with no detectable pathogenicity in mice. 17 As the NHP model is the most relevant animal model for LASV infection, efficacy of a vaccine dose of 2 × 10 7 PFU was assessed in macaques (n = 4). 103 VSVΔG/LASVGPC was well tolerated and no viral shedding occurred after vaccination. Hematology and blood chemistry analysis found a slight thrombocyte decrease as well as a slight elevation of ALT in 3/4 animals. 100% of the animals remained asymptomatic after lethal LASV challenge 28 days after vaccination in contrast to controls, which succumbed to infection, and high LASV-specific antibody titers as well as moderate T-cell responses could be detected. Immunity was not sterile and animals developed viremia that was cleared by day 10. 103 Viremia was, however, not observed in consecutive experiments. 81,104 Another vaccine construct with VSV expressing LASV nucleoprotein (NP) meanwhile only showed limited protection and was not pursued further. 104 The genetic heterogeneity observed between LASV clades raises concerns on whether VSVΔG/LASVGPC can act as a universal vaccine and this question was examined in subsequent studies. In inbred guinea pigs as well as NHPs, vaccination with VSVΔG/LASVGPC resulted in full protection against homologous challenge as well as against challenge with heterologous LASV clade IV isolates 28 days p.v. Again, challenge of inbred guinea pigs with the clade I isolate Pinneo, one of the most genetically divergent isolates compared to Josiah, did not result in clinical disease, while it has to be noted that animals vaccinated with an irrelevant control vector did develop symptomatic disease, but were able to clear infection. 104 Further work to elucidate Lassa crossclade immunity is currently ongoing. 105 A better understanding of the durability of VSVΔG/ LASVGPC is needed to estimate its potential benefit as a vaccine candidate. Stein and colleagues, therefore, sought to examine how early and how long VSVΔG/LASVGPC can confer protection. In a guinea pig-adapted (GPA) LASV model, animals vaccinated with 1 × 10 6 PFU VSVΔG/ LASVGPC were challenged at a timepoint between 7 and 355 days p.v. As early as 7 days p.v. the vaccine provided full protection from clinical disease; however, immunity was not sterile. Antibody responses peaked on day 51 and were sustained until the final sampling date one year later. When challenged 355 p.v., the guinea p