Longitudinal Study of Correlates of Immunity to Tuberculosis in Exposed Individuals
Summary:
Tuberculosis causes 2-3 million deaths each year. A more effective vaccine than
BCG is required, but rational vaccine trials cannot be planned for two main
reasons. Firstly, although many mycobacterial antigens have been isolated, it is
not known which ones to test in human trials and it is not possible to test them
all. Secondly, it is not known which mechanisms are crucial for killing M.
tuberculosis in man, so an adjuvant cannot rationally be selected or short
term pilot studies planned using surrogate markers of protection. VACSEL will,
therefore, conduct longitudinal studies in three geographically distinct African
countries of TB contacts who do or do not develop clinical disease, in order to
identify the antigens, the cytokine profile and the markers of apoptosis that
correlate with protection so that rational design and testing of vaccines can
begin.
Objectives:
The overall objective is to acquire the information needed to allow the
design of tuberculosis vaccines for trial in humans by the end of the project.
This includes antigen selection, rates of transmission and identification of
surrogate markers of protection so that volunteer studies can confirm the
appropriateness of candidate vaccines before proceeding to large, lengthy
protection studies. The specific objectives are:
1) to identify and follow cohorts of tuberculosis-exposed individuals in
three geographically separate African countries
2) to transfer novel reagents and technology to these centres by training
personnel
3) to identify antigens from M. tuberculosis recognised by T cells
from exposed individuals who do and do not develop disease
4) to define cytokine profiles and markers of apoptosis associated with
immunity in fresh, unstimulated, peripheral blood mononuclear cells, and in
antigen-driven cultures.
Description:
VACSEL will transfer technology, reagents and training to three
geographically distinct, high quality African field centres, which have already
identified, or are now defining, cohorts of individuals who have been exposed to
tuberculosis, and either do or do not develop overt disease. Preliminary studies
at one of these centres show that 17% of these contacts may rapidly develop
disease. One of the partners in the consortium has already stored peripheral
blood mononuclear cells from such individuals. SSI has purified antigens from
M. tuberculosis, and identified those that trigger strong T cell
responses. Pilot studies with AHRI have indicated that the pattern of response
to some of these antigens may predict resistance or susceptibility to TB, and it
is crucial that this study is expanded and confirmed in other geographical
locations. To identify the antigens recognised by protected individuals,
lymphoproliferative responses to these antigens will be studied longitudinally
over the course of the project. Supernatants from in vitro culture will
also be used to assay cytokine production by ELISA. UCL will contribute a novel
protocol for sensitive quantitative RT-PCR, which includes a method for rapid
production of standards for any mRNA, and the ability to handle large numbers of
samples. The method readily quantitates background cytokine mRNA expression
levels in fresh, unstimulated, peripheral blood mononuclear cells from normal
donors, and will be used to detect changes in background cytokine expression in
the study cohorts, and the cytokine profile generated in vitro in
response to the candidate antigens provided by SSI. mRNA will be stored,
allowing further cytokines and markers of apoptosis to be studied as they become
identified. This project will further strengthen the research and training
capabilities of the three African centres, all of which are candidate sites for
the eventual TB vaccine trials.
Milestones:
Year 1: a) Train personnel from the field centres. b) Identify cohorts. c)
Start study.
Years 2 and 3: a) Continue longitudinal studies of cohorts. b) Expand
repertoire of antigens and RT-PCR target mRNAs. c) Identify antigens that elicit
responses in immune individuals, and the cytokines and markers of adoptosis
associated with this response pattern. d) Recommendation for vaccine design, and
surrogate markers suitable for pilot studies.
Coordinator:
Alimuddin Zumla
University College London
Department of Bacteriology, Windeyer Institute of Medical Sciences
46 Cleveland Street
W1P 6DB London
United Kingdom
Tel: +44 20 7679 9311
Fax: +44 20 7679 8175
E-mail: a.zumla@ucl.ac.uk
Partners:
- Statens Serum Institut, Department of TB Immunology, DK-Copenhagen, Denmark
- University of Zambia, School of Medicine - UNZA-UCLMS Research and Training Project, Lusaka, Zambia
- Armauer Hansen Research Institute, Addis Ababa, Ethiopia
- Medical Research Council - Malaria Research Programme, UK-London, UK
- Medical Research Council Laboratories, Fajara, Banjul, The Gambia
