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Uncovering correlates of protection of attenuated F. tularensis vaccines

Bowling, Jennifer (2021) Uncovering correlates of protection of attenuated F. tularensis vaccines. Doctoral Dissertation, University of Pittsburgh. (Unpublished)

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Tularemia is a severe zoonotic infection caused by the gram-negative bacterium, Francisella tularensis. Because of the potential for F. tularensis to be weaponized, vaccines and therapeutics are needed. The Live Vaccine Strain (LVS), a type B strain of F. tularensis, was developed as a potential vaccine. Though LVS is able to protect non-human primates and humans against low-dose aerosol exposure to a highly virulent F. tularensis strain, SchuS4 (S4), it is ineffective against high-dose exposure. Due to the unknown mechanism of attenuation, there are concerns that reversion to virulence or batch variation could affect LVS efficacy. We have demonstrated that type A strain S4-based vaccines with mutations in genes encoding metabolic enzymes (S4∆aroD and S4∆guaBA) produce a range of protective efficacy (75% and 50%, respectively) against respiratory challenge with wild type S4 in rabbit model. The mechanisms by which these vaccines provide protection are currently unclear. We have assessed several factors that can influence the interpretation of F. tularensis studies, the role of persistence and dissemination on vaccine efficacy of LVS, S4∆aroD, and S4∆guaBA, and the immune response following vaccination. We have demonstrated sex, growth medium used for challenge material, vaccine schedule, and strain selection are factors that can influence vaccine efficacy studies. S4∆aroD was able to disseminate to the spleen, while LVS and S4∆guaBA were not, though S4∆guaBA persisted in the lung the longest. Microarray analysis of lung, liver, and spleen tissue of S4 infected rabbits show extensive immune suppression, which is consistent with S4 infection in other animal models. In addition to immune suppression, pathways involved in wound healing were suppressed. Cell death pathways, including the inflammasome, were not upregulated following exposure to attenuated F. tularensis strains. These data demonstrate that persistence and dissemination are an important factor in vaccine efficacy while inflammasome activation is not. This work will benefit public health by contributing to the knowledge of immune correlates of protection and rational vaccine design to protect against F. tularensis and other intracellular bacteria.


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Item Type: University of Pittsburgh ETD
Status: Unpublished
CreatorsEmailPitt UsernameORCID
Bowling, Jenniferjeb263@pitt.edujeb2630000-0002-1432-0211
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Committee ChairReed, Douglasdsreed@pitt.edudsreed
Committee MemberMailliard, Robbierbm19@pitt.edurbm19
Committee MemberBility, Mosesmtbility@pitt.edumtbility
Committee MemberMattila, Joshuajmattila@pitt.edujmattila
Date: 27 August 2021
Date Type: Publication
Defense Date: 10 August 2021
Approval Date: 27 August 2021
Submission Date: 14 August 2021
Access Restriction: 1 year -- Restrict access to University of Pittsburgh for a period of 1 year.
Number of Pages: 262
Institution: University of Pittsburgh
Schools and Programs: School of Public Health > Infectious Diseases and Microbiology
Degree: PhD - Doctor of Philosophy
Thesis Type: Doctoral Dissertation
Refereed: Yes
Uncontrolled Keywords: Francisella, tularemia, correlates of protection, vaccines, intracellular bacteria, NZW rabbit
Date Deposited: 27 Aug 2021 18:20
Last Modified: 27 Aug 2022 05:15


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