Vesicular Stomatitis Virus-Based Vaccine Protects Mice against Crimean-Congo Hemorrhagic Fever

Sergio E Rodriguez,Chad E Mire,Dennis A Bente,Robert W Cross,Thomas W Geisbert,Karla A Fenton

doi:10.1038/s41598-019-44210-6

Abstract

Crimean-Congo hemorrhagic fever virus (CCHFV), a tick-borne bunyavirus, can cause a life-threatening hemorrhagic syndrome in humans but not in its animal host. The virus is widely distributed throughout southeastern Europe, the Middle East, Africa, and Asia. Disease management has proven difficult and there are no broadly licensed vaccines or therapeutics. Recombinant vesicular stomatitis viruses (rVSV) expressing foreign glycoproteins (GP) have shown promise as experimental vaccines for several viral hemorrhagic fevers. Here, we developed and assessed a replication competent rVSV vector expressing the CCHFV glycoprotein precursor (GPC), which encodes CCHFV structural glycoproteins. This construct drives strong expression of CCHFV-GP, in vitro. Using these vectors, we vaccinated STAT-1 knock-out mice, an animal model for CCHFV. The vector was tolerated and 100% efficacious against challenge from a clinical strain of CCHFV. Anti-CCHFV-GP IgG and neutralizing antibody titers were observed in surviving animals. This study demonstrates that a rVSV expressing only the CCHFV-GP has the potential to serve as a replication competent vaccine platform against CCHF infections.

Highlights

Full or partial mature Crimean-Congo hemorrhagic fever virus (CCHFV) particles contain single stranded, tri-partite, negative sense RNA genomes with small (S), medium (M), and large (L) segments, respectively encoding the structural nucleoprotein (NP), two envelope proteins (GN and GC) and the viral RNA-dependent-RNA-polymerase (RdRp)[3]
Our initial attempts using the DNA clone recovery system designed by Lawson et al, failed to produce infectious ΔGrVSV with CCHFV-glycoprotein precursor (GPC) (Fig. 1A)[39]
This technique allowed for VSV-G, incorporation into recoveries to facilitate efficient assembly of the rVSVΔG-CCHFV-GPC genome without the need for CCHFV-GPC to participate in initial infection of recovered virions (Fig. 1A)

Summary

Introduction

Full or partial mature CCHFV particles contain single stranded, tri-partite, negative sense RNA genomes with small (S), medium (M), and large (L) segments, respectively encoding the structural nucleoprotein (NP), two envelope proteins (GN and GC) and the viral RNA-dependent-RNA-polymerase (RdRp)[3]. The two glycoproteins are likely responsible for pertinent events in the viral replication cycle such as viral attachment, cell entry, tissue tropism(s), and induction of protective immune response as seen with other members of Bunyavirales[13,14] The latter has been demonstrated for CCHFV using monoclonal antibodies (MAb) directed against GN and GC, which have demonstrated in vitro neutralization in tissue culture and in vivo passive protection in suckling mice[13,14,15]. The aim of our study was to design, generate, characterize, and evaluate a rVSV vector encoding the CCHFV-GPC as an experimental vaccine for CCHFV

Objectives

Methods

Results

Conclusion