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Determination of correlates of protection against tuberculosis in nonhuman primate models

DiFazio, Robert M. (2017) Determination of correlates of protection against tuberculosis in nonhuman primate models. Doctoral Dissertation, University of Pittsburgh. (Unpublished)

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Abstract

Tuberculosis (TB) is one of the greatest global health challenges society faces. BCG, the only licensed vaccine for TB, has profoundly variable efficacy and does not prevent the spread of TB. Due to the lack of an effective vaccine, there are no correlates of protection to use in vaccine development. The goal of this dissertation was to develop new tools for pre-clinical and clinical trials of TB vaccines, including new outcome measures and predictive markers of efficacy. Development of these tools will expedite down-selection of vaccinate candidates, reducing their ultimate cost and hastening the reduction and eventual elimination of this disease. BCG afforded the best levels of protection in the rhesus macaque model of TB, which closely resembled TB disease in human infants. Boosting BCG by protein antigens or adenoviral vectored antigens did not improve, and in some cases worsened, outcome. A T cell signature in the lung-draining lymph nodes (LN) at necropsy, early gamma interferon (IFN-γ) ELISPOT and early PET-CT markers correlated with improved outcome in this model. We further characterized the protection afforded by an experimental boost to BCG, H56, which has been shown to prevent reactivation TB in cynomolgus macaques. BCG/H56 prevented establishment of disease in lung- draining LN. BCG/H56 also mitigated lung inflammation, which reduced apparent risk of reactivation TB by PET-CT. Early control of disease in the lung-draining LN, as well as a T cell signature, was associated with reduced risk of reactivation TB. Both studies provided evidence that PET-CT markers correlate with outcome. We thus built a holistic outcome score based iv
strictly on quantifiable outcomes: gross pathology and bacterial burden determined at necropsy, and constructed models that robustly predict this outcome score early using early PET-CT markers. Altogether, these studies highlight the importance of the lung-draining LN as a site of bacterial persistence and the ability of PET-CT to assess disease and predict vaccine efficacy. Further work will build upon these studies to determine the best site of vaccination to prevent disease, and develop a blood signature correlate for use in clinical trials.


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Details

Item Type: University of Pittsburgh ETD
Status: Unpublished
Creators/Authors:
CreatorsEmailPitt UsernameORCID
DiFazio, Robert M.rod28@pitt.eduROD280000-0003-0592-0335
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Committee ChairFlynn, JoAnne L.joanne@pitt.eduJOANNE
Committee MemberNorris, Karen A.kan1@pitt.eduKAN1
Committee MemberBarratt-Boyes, Simon M.smbb@pitt.eduSMBB
Committee MemberMorel, Penelope Amorel@pitt.eduMOREL
Committee MemberAnderson, Carolyn Jcja34@pitt.eduCJA34
Date: 18 January 2017
Date Type: Publication
Defense Date: 2 December 2016
Approval Date: 18 January 2017
Submission Date: 15 December 2016
Access Restriction: 3 year -- Restrict access to University of Pittsburgh for a period of 3 years.
Number of Pages: 219
Institution: University of Pittsburgh
Schools and Programs: School of Medicine > Molecular Virology and Microbiology
Degree: PhD - Doctor of Philosophy
Thesis Type: Doctoral Dissertation
Refereed: Yes
Uncontrolled Keywords: tuberculosis; nonhuman primates; vaccines; PET-CT
Date Deposited: 18 Jan 2017 20:34
Last Modified: 18 Jan 2017 20:34
URI: http://d-scholarship.pitt.edu/id/eprint/30582

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