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MUCOSAL TB VACCINE
TUBERCULOSIS
Framework programme: 5
Project number:
QLK2-CT-1999-00367
EC contribution: € 1 078 845
Duration: 36 months
Type: RS
Starting date: 1 February 2000
Graphic element Role of Mucosal Immunity for Protection against Tuberculosis
Keywords: Tuberculosis; mucosal immunity; mucosal vaccination; T-cell immunology; vaccine

Summary:

Tuberculosis (TB) is a re-emerging disease, and has been designated a ‘global health emergency’ by the World Health Organisation. The current vaccine (BCG) is not fully effective, and so there is a need to develop a more effective vaccine. The aim of the project is to determine whether an improved vaccine against TB can be designed by inducing mucosal immunity directly in the lung. The project involves collaboration between microbiologists and immunologists to develop new vaccine candidates and novel routes of delivery to achieve enhanced protection in the lung.

Problem:

Over recent years, TB has re-emerged as one of the leading causes of death (nearly 3 million die annually). In humans, the main cause of TB is infection following inhalation of the intracellular pathogen, Mycobacterium tuberculosis. Some of these strains are now resistant to a number of front-line antibiotics. Vaccination is one approach to control this disease. However, the current vaccine (BCG) does not protect all age groups, its efficacy is globally variable, and it does not provide protection in many Third World countries where TB is prevalent. BCG is also a live vaccine, and is not suitable for use with immuno-compromised patients. In addition, BCG reduces dissemination of M. tuberculosis to the spleen and other organs, but does not prevent mycobacterial growth in the lungs. Therefore, an improved vaccine is required.

Previous and current attempts to produce a more effective vaccine have been generally focused on inducing a cell-mediated immune response to kill the intracellular bacilli. So far, however, these approaches have not produced a vaccine that has induced protection significantly better than BCG, suggesting that a more novel vaccine strategy is required. As an example, it has been demonstrated recently that mucosal antibodies (particularly IgA) can inhibit the growth of intracellular pathogens. These and other findings are being applied in these studies to develop a more effective TB vaccine.

Aim:

The aim is to develop a more effective vaccine strategy against TB, based on the induction of an appropriate immune response on mucosal surfaces in the lung. This will be achieved by:

  • Understanding the immune mechanisms (cellular and humoral) that may correlate with protection in the lung. These studies will focus on the role of specific antibodies, as well as the role of ab- and gd-T cells, in modulating the growth of, and cell invasion by, M. tuberculosis;
  • Producing purified antigens (proteins and DNA) suitable for mucosal delivery;
  • Optimising  the nasal delivery of these antigens to achieve an effective immune response in the lung;
  • Evaluating the protection in relevant aerosol infection models of TB.

Expected results:

  1. A definitive, proof-of-principle assessment as to whether mucosal immunity, including specific antibodies in the lung, play a role in protection against TB.
  2. An assessment of the feasibility of passive immunisation against TB.
  3. An assessment of the pattern of cell invasion during the early stages of infection by Mycobacterium tuberculosis.
  4. The production of a range of purified subunit antigens for use as vaccine candidates.
  5. The optimisation of a nasal vaccination regime for both BCG and antigen subunits in order to induce a protective immune response in the lung. This would include an analysis of the humoral and T-cell responses (including ß- and d-T cells) in the lung.

Potential applications:

The study intends to develop a novel vaccination approach to provide improved protection against TB. The study is providing insights that could be used in the future in both passive and active vaccination strategies. The results may also influence the development of vaccines against other intracellular pathogens. The data generated by this project will be of value to pharmaceutical companies with an interest in the control of mucosal pathogens.

Coordinators:

P. D. Marsh
CAMR
SP4 0JG Salisbury
United Kingdom
Tel: +44 1980 612287
Fax: +44 1980 612731
E-mail: phil.marsh@camr.org.uk

A. Rawkins
CAMR
SP4 0JG Salisbury
United Kingdom
Tel: +44 1980 612287
Fax: +44 1980 612731
Website: http://www.camr.org.uk

Partners:

Principal
Scientific
Participants
Official Address Other Information
2J. Ivanyi
S. Challacombe
J. Ma
R. Reljic
Division of Oral Medicine, Immunology, Microbiology and Pathology
Kings College London
Guys Campus, London Bridge
UK-SE1 9RT London
United Kingdom
Tel: +44 207 7188 4374
Fax: +44 207 7188 4375
E-mail: juraj.ivanyi@kcl.ac.uk
3C. Fernandez
N. Troye-Blomberg
A. Rodriguez
Department of Immunology
Stockholm University,
SE-106 91 Stockholm
Sweden
Tel: +46 8 164599
Fax: +46 8 154163
E-mail: carmen.fernandez@imun.su.se
4F. Dieli
A. Salerno
Instituto di Metologie Diagnostiche Avanzate
Corso Tukory 211
IT-90134 Palermo
Italy
Tel: +39 091 655 5902
Fax: +39 091 655 5901
E-mail: dieli@unipa.it
5M. Singh
M. Comini
Department of Biochemistry
Department of Biochemistry, 458
TU-BS, Mascheroder Weg 1
DE-38124 Braunschweig
Germany
Tel: +49 531 6181 320
Fax: +49 531 2601 159
E-mail: msi@gbf.de

 
 
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