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Determining the Innate and Adaptive Immune Responses to Vesicular Stomatitis Virus Vaccine Vectors

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abstract
Vesicular stomatitis virus (VSV) vaccine vectors have been engineered to express many different antigens. Studies in mice and nonhuman primates have demonstrated efficacy against several pathogens. A novel strategy to enhance VSV as an effective vaccine is to engineer vectors that induce innate immune mechanisms. We have generated an improved VSV vaccine vector that incorporates two enhancing strategies; an M protein mutation (M51R) that prevents the virus from suppressing host responses and the addition of a vaccine adjuvant, bacterial flagellin, expressed intracellularly from the viral genome (M51R-F). The ability of the vectors to induce innate immune responses was tested in murine dendritic cells. The presence of flagellin led to production of IL-1beta; and an inflammatory form of cell death called pyroptosis that were not induced by control vectors. Flagellin signalling was determined to be through the sensor, NLRC4. Previous studies have shown that expression of flagellin enhanced the antibody response in murine in vivo models. My experiments analyzed the T-cell responses in mice vaccinated intranasally with M51R or M51R-F. Results showed no significant difference between M51R and M51R-F vectors in either CD8+ or CD4+ T-cell responses. To address the memory phase mice were vaccinated with M51R or M51R-F and 40 days later challenged intranasally with vaccinia virus expressing VSV proteins. Mice vaccinated with M51R or M51R-F had significantly more IFN-y producing CD8 T-cells than mock vaccinated mice. However, there was no statistical difference between M51R and M51R-F vectors. These results show that VSV vectors are effective vaccines, even with minimal effects of flagellin expression on T cell responses.
subject
Vaccine
VSV
contributor
Smedberg, Jason (author)
Lyles, Douglas S (committee chair)
Alexander-Miller, Martha (committee member)
Daniel, Larry (committee member)
Hollis, Thomas (committee member)
date
2014-07-10T08:35:36Z (accessioned)
2014-07-10T08:35:36Z (available)
2014 (issued)
degree
Biochemistry and Molecular Biology (discipline)
identifier
http://hdl.handle.net/10339/39297 (uri)
language
en (iso)
publisher
Wake Forest University
title
Determining the Innate and Adaptive Immune Responses to Vesicular Stomatitis Virus Vaccine Vectors
type
Dissertation

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