Vesicular stomatitis virus (VSV) is a cytopathic virus that has been developed as a vaccine vector due to its ability to induce strong, protective antibody and T cell responses to encoded foreign antigens after a single dose. VSV efficiently incorporates glycoproteins ( GP) from a different virus on virion surface allowing production of replication-competent recombinant vectors in which the cognate VSV G gene is replaced by a foreign GP gene. Recombinant VSVs (rVSVs) expressing foreign GPs have been studied as vaccine vectors for a number of pathogens including the recent successful deployment of a rVSV-Ebola vaccine. Despite this success, studies in animal models demonstrate significant pathogenic effects when some rVSV are injected intracerebrally or when used to infect animals with defective interferon responses. Concerns raised by these studies support development of more attenuated rVSV vectors with better safety profiles.
Specific Aim 1 will utilize a novel strategy for attenuating rVSV vaccine vectors by joining adjacent VSV transcripts using a P2A ribosomal skipping sequence between adjacent genes in the VSV genome. rVSV with single or multiple fused transcripts will be tested for pathogenesis in immunocompromised mouse models or in the CNS.
In Specific Aim 2 these next generation, low pathogenicity vectors expressing the glycoproteins of Severe Fever with Thrombocytopenia Syndrome virus (SFTSV) will be analyzed for their ability to induce neutralizing responses. SFTSV is a pathogenic, tick-transmitted bunyaviruses that causes a severe febrile hemorrhagic-like disease with case fatality rates of up to 30%. Initially discovered during a 2009 outbreak of febrile illness in China, the geographic distribution of SFTSV extends into Korea and Japan. There are currently no vaccine or therapeutics for SFTSV. Because of its potential threat the WHO included SFTSV in its 2017 recommendation ?A research and development Blueprint for action to prevent epidemics? and identified SFTSV as one of 11 pathogens most likely to cause severe outbreaks in the near future and proposed development of vaccines. Included in this revised application are preliminary data demonstrating induction of strong neutralizing antibody responses that correlate with protection from SFTSV challenge in mice vaccinated with a 1st generation rVSV-SFTSV. Additionally, vaccination of IFNAR-/- mice with the 1st generation rVSV-SFTSV demonstrated significant pathology (weight loss) supporting the premise for Aim 1. This short IDEA proposal is designed to produce attenuated rVSV vectors useful for vaccine development for many pathogens and will generate proof-of-principle data that will permit further development of a vaccine for SFTSV.

Public Health Relevance

Within this proposal we will develop next generation, highly attenuated recombinant vesicular stomatitis viruses (VSVs) as vaccine vectors. These vectors will be evaluated for their ability to induce neutralizing antibodies to the surface proteins of Severe Fever with Thrombocytopenia virus (SFTSV) ? a highly pathogenic, tick-transmitted virus that causes a severe hemorrhagic disease. In addition to providing proof-of-principle for an SFTSV vaccine, development of these improved viral vaccine vectors with a better safety profile will be applicable to numerous vaccine efforts.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Exploratory/Developmental Grants (R21)
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Vaccines Against Microbial Diseases Study Section (VMD)
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Alarcon, Rodolfo M
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University of Pennsylvania
Schools of Medicine
United States
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