Development of recombinant VSV vaccines for emerging bunyaviruses

PROJECT SUMMARY/ABSTRACT Emerging viral infections remain a global threat to human health. Bunyaviruses are the largest order of RNA viruses that includes many clinically relevant human pathogens such as Lassa, Rift Valley Fever and various hantaviruses which cause viral hemorrhagic fever (VHF). SFTSV, or Severe fever with thrombocytopenia syndrome virus, is an emerging tick-borne bunyavirus that has caused outbreaks in Eastern Asia (China, Japan, Korea, Vietnam) with up to a 30% case fatality rate. The host tick vector has now been discovered over a large geographical setting and SFTSV has been found in numerous wild and domestic animal species highlighting a risk for zoonotic spillover into humans. Though humans are usually dead-end hosts, human to human transmission has been documented through blood and mucosal secretions. Furthermore, SFTSV has a segmented genome which increases ability to reassort genes and mutate. Due to these features, in its 2017 "Research and Development Blueprint" the WHO identified SFTSV as one of 11 pathogens likely to cause a sever outbreak in the future. As we have learned, from experience with recent zoonotic outbreaks, preparedness is of the utmost importance. We are proposing to continue development of a recombinant vesicular stomatitis virus (rVSV)-based vaccine for SFTSV. rVSV is an approved vaccination platform that is immunogenically potent and proven tolerable. Preliminary work from our group has demonstrated that rVSV-SFTSV can elicit protection in mice, is tolerable in immunocompromised animals and upon CNS injection, and can generate cross protecting responses to a related bunyavirus. Furthermore, we observe elevated SFTSV-specific T cell and antibody responses against both SFTSV spike proteins, Gn and Gc. In this Phase I, we propose to improve the design of our vector which will increase viral titers to facilitate vaccine manufacturing and increase immunogenicity in animals. In aim 1, we will focus on reverse engineering mutations into rVSV that will improve SFTSV Gn/Gc incorporation into particles thereby improving virus replication and yield in vitro. We will characterize these 2nd generation (Gen2) vaccines using molecular and cell-based assays scoring for viral replication, GnGc expression in infected cells and incorporation of GnGc in VSV virions. In aim 2, we will assess the ability of our Gen2 vaccine to protect animals in lethal SFTSV challenge studies. We hypothesize that increased GnGc expression and replication of the Gen2 vectors will lead to improved immune responses in vaccinated animals compared to the Gen1 vector. We will assess immune correlates of protection such enhanced neutralizing and cross protective antibodies as well as robust T cell responses compared to Gen1 rVSV-SFTSV vaccinated animals. If successful, our Phase I would set the foundation for a Phase II to advance manufacturing and stringently study protective capacity of our vaccine in more advanced animal models.