Our objective is a better understanding of vaccination-induced protection against tuberculosis (TB) in humans. This knowledge is critical for developing novel TB vaccines.
Our first aim i s to characterize T cell immunity following BCG vaccination of newborns. We will focus on longitudinal changes in specific CD4+ and CD8+ T cell immunity conventionally associated with protection against TB. We will test the hypothesis that regulatory CD4+ T cells are induced by BCG, and that these cells modulate specific immune outcome. Newly validated whole blood assays will be used to measure immunity in infants from South Africa, where vaccination with BCG at birth is routine, and where the TB incidence is very high. Complementary, longitudinal studies of adults vaccinated with BCG will also be performed, as larger blood volumes will allow a more comprehensive functional immune assessment.
Our second aim i s to identify immune components that are associated with BCG-induced protection against infant TB. To address this aim, we have already collected processed and stored blood from 5,675 10-week old South African infants, vaccinated with BCG at birth. We have subsequently identified >500 of these infants who have developed TB disease (cases), or who have remained healthy despite exposure to adults with TB (controls). We will retrieve stored blood of cases and controls, and compare conventional and regulatory immunity induced by BCG. Additionally, we hypothesize that we will identify novel genes involved in BCG-induced protection against TB, with DNA micro-array analysis.
Our third aim i s to determine whether the antibody response to BCG contributes to protection against TB. We will characterize this response in newborns vaccinated with BCG. We will compare the antibody response between BCG-vaccinated infants who are protected against TB, and those not protected.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
1R01AI065653-01
Application #
6958747
Study Section
Special Emphasis Panel (ZRG1-VMD (01))
Program Officer
Sizemore, Christine F
Project Start
2005-07-14
Project End
2010-03-31
Budget Start
2005-07-14
Budget End
2006-03-31
Support Year
1
Fiscal Year
2005
Total Cost
$464,267
Indirect Cost
Name
University of Cape Town
Department
Type
DUNS #
568227214
City
Rondebosch
State
Country
South Africa
Zip Code
7700
Hasso-Agopsowicz, Mateusz; Scriba, Thomas J; Hanekom, Willem A et al. (2018) Differential DNA methylation of potassium channel KCa3.1 and immune signalling pathways is associated with infant immune responses following BCG vaccination. Sci Rep 8:13086
Fletcher, Helen A; Filali-Mouhim, Ali; Nemes, Elisa et al. (2016) Human newborn bacille Calmette-Guérin vaccination and risk of tuberculosis disease: a case-control study. BMC Med 14:76
Dintwe, One B; Day, Cheryl L; Smit, Erica et al. (2013) Heterologous vaccination against human tuberculosis modulates antigen-specific CD4+ T-cell function. Eur J Immunol 43:2409-20
Kalsdorf, Barbara; Skolimowska, Keira H; Scriba, Thomas J et al. (2013) Relationship between chemokine receptor expression, chemokine levels and HIV-1 replication in the lungs of persons exposed to Mycobacterium tuberculosis. Eur J Immunol 43:540-9
Matthews, Kerryn; Wilkinson, Katalin A; Kalsdorf, Barbara et al. (2011) Predominance of interleukin-22 over interleukin-17 at the site of disease in human tuberculosis. Tuberculosis (Edinb) 91:587-93
Day, Cheryl L; Abrahams, Deborah A; Lerumo, Lesedi et al. (2011) Functional capacity of Mycobacterium tuberculosis-specific T cell responses in humans is associated with mycobacterial load. J Immunol 187:2222-32
Shey, M S; Randhawa, A K; Bowmaker, M et al. (2010) Single nucleotide polymorphisms in toll-like receptor 6 are associated with altered lipopeptide- and mycobacteria-induced interleukin-6 secretion. Genes Immun 11:561-72
Scriba, Thomas J; Tameris, Michele; Mansoor, Nazma et al. (2010) Modified vaccinia Ankara-expressing Ag85A, a novel tuberculosis vaccine, is safe in adolescents and children, and induces polyfunctional CD4+ T cells. Eur J Immunol 40:279-90
Soares, Andreia; Govender, Lerisa; Hughes, Jane et al. (2010) Novel application of Ki67 to quantify antigen-specific in vitro lymphoproliferation. J Immunol Methods 362:43-50
Tena-Coki, Nontobeko G; Scriba, Thomas J; Peteni, Nomathemba et al. (2010) CD4 and CD8 T-cell responses to mycobacterial antigens in African children. Am J Respir Crit Care Med 182:120-9

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