Development Of Novel Vaccination Strategies Against Emerging Bunyaviruses

Loading...
Thumbnail Image
Degree type
Doctor of Philosophy (PhD)
Graduate group
Cell & Molecular Biology
Discipline
Subject
Allergy and Immunology
Immunology and Infectious Disease
Medical Immunology
Microbiology
Virology
Funder
Grant number
License
Copyright date
2022-10-05T20:22:00-07:00
Distributor
Related resources
Author
Manzoni, Tomaz
Contributor
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.

Advisor
Paul Bates
Date of degree
2022-01-01
Date Range for Data Collection (Start Date)
Date Range for Data Collection (End Date)
Digital Object Identifier
Series name and number
Volume number
Issue number
Publisher
Publisher DOI
Journal Issue
Comments
Recommended citation