The overall objective of the Cluster is to establish a framework for preclinical development of novel tuberculosis vaccine candidates. We aim to identify optimal strategies for generation of vaccine candidates by comparing innovative approaches based on identification of novel protein antigens, characterisation of non-protein antigens that elicit T cell responses in man, and construction of live attenuated strains of mycobacteria. New vaccines will be compared alone or in combination in standardised experimental challenge models to identify candidates superior to the existing BCG vaccine. In parallel, the immunological mechanisms underlying vaccine-induced protection will be characterised in man and in experimental models. This information will be used to develop immunological tests for initial clinical assessment of new vaccines. Integration of these activites, with the participation of the top academic and industrial researchers in Europe (Aventis Pasteur, SmithKline Beecham and the Statens Serum Institut), is essential for completion of the final goal of bringing one or more new vaccines to a stage suitable for clinical trials.
The workplan for the Cluster is based on five interactive component
Projects. Project 1 will focus on establishment of a standardised protocol
for preclinical assessment of vaccine candidates in a series of animal challenge models. Protein antigens with known vaccine potential will be used for comparative evaluation of delivery systems based on novel adjuvants, DNA constructs, and attenuated viral vectors. Candidates that perform optimally in naive challenge models in mice and guinea pigs will be taken forward into screening in bovine and primate models. Projects 2 and 3 are directed towards discovery of new vaccine candidates which will subsequently feed into the preclinical screening programme established in Project 1. Participants in Project 2 will use powerful new tools for genetic manipulation of mycobacteria to construct a new generation of live attenuated mycobacterial vaccines. These will include recombinant BCG strains optimised for immunogenicity and safety, as well as M. tuberculosis strains lacking key virulence determinants following random transposon mutagenesis or predictions from bioinformatic and comparative genomic analysis. Project 3 will focus on novel non-protein antigens from mycobacteria that have recently been demonstrated to induce human T cell responses. A key aspect of the Cluster is that each of these strategies can be pursued simultaneously and that the different classes of candidate can be directly compared against each other and in combination. Finally, participants in Project 4 will study the mechanisms underlying the pathological manifestations of tuberculosis and the protective immune responses induced by the different vaccine candidates. This will identify immunological tests suitable for initial assessment of new vaccines in clinical trials.
Funding SchemeCSC - Cost-sharing contracts
2280 GH Rijswijk Zh
8219 PH Lelystad
2300 RC Leiden
SP4 0JG Salisbury
NW7 1AA London
OX3 9DU Oxford/headington
KT15 3NB Addlestone
BT4 3SD Belfast
AL9 7TA Welham Green,hatfieid
GU2 5XH Guildford