Advanced vaccine candidates for Lassa fever

Abstract

Lassa virus (LASV) is the most prominent human pathogen of the Arenaviridae. The virus is transmitted to humans by a rodent reservoir, Mastomys natalensis, and is capable of causing lethal Lassa Fever (LF). LASV has the highest human impact of any of the viral hemorrhagic fevers (with the exception of Dengue Fever) with an estimated several hundred thousand infections annually, resulting in thousands of deaths in Western Africa. The sizeable disease burden, numerous imported cases of LF in non-endemic countries, and the possibility that LASV can be used as an agent of biological warfare make a strong case for vaccine development. Presently there is no licensed vaccine against LF or approved treatment. Recently, several promising vaccine candidates have been developed which can potentially target different groups at risk. The purpose of this manuscript is to review the LASV pathogenesis and immune mechanisms involved in protection. The current status of pre-clinical development of the advanced vaccine candidates that have been tested in non-human primates will be discussed. Major scientific, manufacturing, and regulatory challenges will also be considered.

Figure 1 (a)

Risk map of Lassa Fever in West Africa. Positive localities indicated by stars. The posterior probability color scale, from 0.0 (no risk) to 1.0 (highest risk) is shown as an inset. From E. Fichet-Calvet, D.J. Rogers [3] with permission.

Figure 1 (b)

Phylogenetic relationships among the Old World arenaviruses (grey sector) based on analysis of the NP gene. From A. Ishii et al with permission [10]. See text for more details.

Figure 2

Advanced alphavirus-based vector technology. The 1st generation was based on Venezuelan equine encephalitis virus (VEEV) and required BSL-3 containment. Replication-competent virus (RCV) can be generated during a recombination event. In the 2nd generation, vectors use human vaccine VEEV TC-83 vaccine backbone and transcription of helper genes is controlled by non-related CMV (cytomegalovirus) promoter. Helper proteins (capsid and glycoproteins, E1&E2) can be made from two mono-cistronic CMV-plasmids or from one CMV-bicistronic plasmid (see text). Recombination events are minimized and BSL2 containment is required for production ([126]; Pushko & Lukashevich, unpublished.

Figure 3

The predicted structure of GP2 glycoprotein of ML29. The non-conservative K272E substitution (marked by star) located between two fusion domains at N-terminus introduced two negatively charged groups in positions 272-273 (Asp-Glu) resulted in refolding and exposure of transmembrane and cytoplasmic domains. Protein structure prediction was performed using the Phyre server (http://www.sbg.bio.ic.ac.uk/phyre2/html/page.cgi?id=index) [173].

Figure 4

(A), Survival rate of strain 13 guinea pigs (4 animals per group) fatally infected with LASV (Jos, 1000 PFU, s.c.) and treated on day 2 and 4 after challenge with ML29 (1000 PFU, s.c.); (B), ML29 preventive efficacy in common marmosets. Animals (6 animals per group) were vaccinated with ML29 and challenged on day 30 with LASV (Jos) [143].