A single-cycle replicable Rift Valley fever phlebovirus vaccine carrying a mutated NSs confers full protection from lethal challenge in mice

Kaori Terasaki,Shinji Makino,Jennifer K Smith,Alexander N Freiberg,David D Perez,Terry L Juelich,Birte Kalveram

doi:10.1038/s41598-018-35472-7

Kaori Terasaki, Shinji Makino + Show 5 more

Open Access

https://doi.org/10.1038/s41598-018-35472-7

Copy DOI

Abstract

Rift Valley fever phlebovirus (RVFV) is a pathogen of Rift Valley fever, which is a mosquito-borne zoonotic disease for domestic livestock and humans in African countries. Currently, no approved vaccine is available for use in non-endemic areas. The MP-12 strain is so far the best live attenuated RVFV vaccine candidate because of its good protective efficacy in animal models. However, there are safety concerns for use of MP-12 in humans. We previously developed a single-cycle replicable MP-12 (scMP-12) which lacks NSs gene and undergoes only a single round of viral replication because of its impaired ability to induce membrane-membrane fusion. In the present study, we generated an scMP-12 mutant (scMP-12-mutNSs) carrying a mutant NSs, which degrades double-stranded RNA-dependent protein kinase R but does not inhibit host transcription. Immunization of mice with a single dose (105 PFU) of scMP-12-mutNSs elicited RVFV neutralizing antibodies and high titers of anti-N IgG production and fully protected the mice from lethal wild-type RVFV challenge. Immunogenicity and protective efficacy of scMP-12-mutNSs were better than scMP-12, demonstrating that scMP-12-mutNSs is a more efficacious vaccine candidate than scMP-12. Furthermore, our data suggested that RVFV vaccine efficacy can be improved by using this specific NSs mutant.

Highlights

Rift Valley fever phlebovirus (RVFV) is an arbovirus of major public health concern in African and Middle Eastern countries
Mice immunized with 105 PFU of single-cycle replicable MP-12 (scMP-12)-mutNSs elicited higher anti-N antibody titers than those immunized with 105 PFU of scMP-12
The number of mice that survived from wt RVFV challenge was significantly higher among mice immunized with 104 PFU of scMP-12-mutNSs than those immunized with the same dose of scMP-12

Summary

Introduction

RVFV is an arbovirus of major public health concern in African and Middle Eastern countries. The numbers in the middle panels indicate the relative band intensities of the N protein signals in scMP-12 and scMP-12-mutNSs-infected cells. (d) Single-cycle property of scMP-12-mutNSs. Left panel: Culture supernatant of scMP-12-mutNSs-infected BHK cells, which was used for (f), was inoculated into VeroE6 cells without dilution for plaque assay. Age-dependent susceptibility to RVFV has been reported in rats and gerbils[21,22,23] Consistent with this notion, RVFV infection causes high mortality rates in young ruminants[19,24]. RVFV vaccine developments primarily focus on the efficient expression or delivery of Gn/Gc, which carry virus neutralizing epitopes[27], in immunized animals to induce high titers of neutralizing antibodies. Recent works[36,37] identified epitopes in N protein for CD4+ T cells, which play a role in the clearance of RVFV from infected tissues[38], and for CD8+ T cells, which possibly activate cell mediated immunity upon RVFV infection

Methods

Results

Conclusion