Date of Award

2022

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Graduate Group

Cell & Molecular Biology

First Advisor

Paul Bates

Abstract

Severe fever with thrombocytopenia syndrome virus (SFTSV) is a highly pathogenic emergent bunyavirus. First isolated in 2009 in China, SFTSV is now endemic to several east Asian countries where high case fatality ratios of 6-30% are reported. The primary tick vector of SFTSV, Haemaphysalis longicornis, has a large range and is a well reported invasive species throughout the world. This, in addition to SFTSV’s ability to spread in the absence of its vector in nosocomial and veterinary settings, suggests SFTSV is well suited to cause widespread lethal outbreaks. Currently no vaccines or therapeutics against SFTSV exist, prompting health agencies to list SFTSV as a high priority pathogen. Here, we first develop a single dose recombinant vesicular stomatitis virus (rVSV) encoding the SFTSV glycoproteins Gn/Gc as a virus vectored vaccine. We demonstrate that this vaccine (rVSV-SFTSV) is safe in immunocompromised mice and not neuropathogenic when delivered intracerebrally. Additionally, this vaccine induces robust antibody responses that are protective from lethal challenge. Furthermore, we demonstrate that this vaccine elicits cross-protective responses against the closely related Heartland virus. We then developed an mRNA vaccine encoding SFTSV Gn/Gc and compared this platform with our rVSV-SFTSV vaccine in single dose, homologous prime-boost, and heterologous prime-boost regimens. We found that mRNA immunizations in single dose and homologous prime-boost regimens achieved the highest neutralizing antibody titers. Immunizations with rVSV-SFTSV also reached high antibody titers though they were the lowest titers of any immunization regimen, with heterologous prime-boost having intermediate titers. When T-cell responses were analyzed, mRNA immunization achieved robust CD4+ and CD8+ responses in single dose and homologous prime-boost regimens. Heterologous vaccine regimens elicited similar responses to homologous mRNA strategies despite weak cellular activity after rVSV-SFTSV prime. Despite some differences in immunogenicity, all vaccines were protective from lethal SFTSV challenge. Overall, this work demonstrates the effectiveness of two vaccine platforms in their ability to elicit robust protective responses against SFTSV.

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