Preclinical Safety Assessment of the EBS-LASV Vaccine Candidate against Lassa Fever Virus

Abstract

There are currently no prophylactic vaccines licensed to protect against Lassa fever caused by Lassa virus (LASV) infection. The Emergent BioSolutions (EBS) vaccine candidate, EBS-LASV, is being developed for the prevention of Lassa fever. EBS-LASV is a live-attenuated recombinant Vesicular Stomatitis Virus (rVSV)-vectored vaccine encoding the surface glycoprotein complex (GPC) from LASV and has two attenuating vector modifications: a gene shuffle of the VSV N gene and a deletion of the VSV G gene. Preclinical studies were performed to evaluate EBS-LASV's neurovirulence potential following intracranial (IC) injection and to determine the biodistribution and vector replication following intramuscular (IM) inoculation in mice. In addition, the potential EBS-LASV toxicity was assessed using repeated-dose IM EBS-LASV administration to rabbits. All mice receiving the IC injection of EBS-LASV survived, while mice administered the unattenuated control vector did not. The vaccine was only detected in the muscle at the injection site, draining lymph nodes, and the spleen over the first week following IM EBS-LASV injection in mice, with no detectable plasma viremia. No toxicity was observed in rabbits receiving a three-dose regimen of EBS-LASV. These studies demonstrate that EBS-LASV is safe when administered to animals and supported a first-in-human dose-escalation, safety, and immunogenicity clinical study.

Keywords: LASV; Lassa virus; VSV; attenuated vaccine; biodistribution; glycoprotein; neurovirulence; preclinical safety; vesicular stomatitis virus.

Figure 1

Genome organization of attenuated rVSV LASV vaccine candidate. (A) Organization of the wild-type VSV genome showing the nucleocapsid protein (N), phosphoprotein (P), matrix protein (M), glycoprotein (G), and large protein (L). The numbers indicate the genomic position of the transcriptional unit containing the individual open reading frame. The virus leader (Le), trailer (Tr), and gene junctions are shown in black. (B) Genome organization of the EBS-LASV vaccine candidate [rVSV-N4ΔG-LASV-GPC1]. The VSV N gene was shuffled to the 4th position (N4), the Lassa glycoprotein complex (GPC) gene was placed in the first position (GPC1), and the transcriptional cassette containing the VSV G gene was deleted from the virus genome (ΔG).

Figure 2

Plaque assay results from mouse biodistribution study. The LLOQs for the brain and liver were higher than depicted above; however, all levels were below the LLOD. LLOQ = lower limit of quantitation; LLOD = lower limit of detection.

Figure 3

Rabbit body weight data. (A) Summary of male body weights; (B) summary of female body weights.

Figure 3

Rabbit body weight data. (A) Summary of male body weights; (B) summary of female body weights.

Figure 4

Rabbit serum LASV GP IgG endpoint titers (geomean ± 95%CI on Study Days −7, 22, and 43). (A) Geometric mean endpoint titers of saline control and EBS-LASV groups. (B) Geometric mean endpoint titers of male and female rabbits within each group. * p = 0.0054 at t-test.