| In line with NACCAP's objectives, this project focuses on tuberculosis (TB) as one of the major infectious diseases that scourges sub-Saharan Africa, including Tanzania and Ethiopia, particularly in the context of HIV/AIDS. The development of improved tools for diagnosing, treating and vaccinating against TB are urgently needed to combat TB/HIV. Several large international networks, in which the applicants participate, are addressing these issues. The tools developed will need to be tested and evaluated in clinical trials in Africa, especially in HIV-infected individuals, before they can be implemented. However, the R&D capacity in many African countries is insufficient to perform such studies, implicating that evaluation of new tools and interventions will suffer from unnecessary delays and cost many lives. To help removing these roadblocks, we aim to strengthen the R&D capacity in the field of TB by investing in sustainable joint research activities and clinical testing in Africa at locally owned R&D centers. The objectives of this project are: 1) To build and develop capacity to conduct clinical (TB-)trials in Tanzania (KCMC Clinical Research Center (KCRC)) and Ethiopia (ALERT-AHRI/MoH). A phase-I/IIa clinical trial center will be established at KCMC together with other groups in APRIORI (as outlined in part A). These activities will focus on creating physical capacity, training staff, developing laboratory infrastructure, improving microbiological and immuno-diagnostics, promoting GCP- and ethics-infrastructure, and will involve north-south as well as south-south capacity building activities. Activities will encompass MSc/PhD-student exchange between AHRI-KCMC, GCP workshops on ethics with facilitators from Mali, Tanzania and Ethiopia (AHRI hosts the secretariat for the Pan-African Bioethics Initiative (www.pabin.net)), local coaching by NL-researchers as well as MSc-student exchange. The major deliverable is the establishment of a clinical trial centre according to GCP/GLP standards that is sustainable and competitive in attracting products, including vaccines, for clinical testing. In Ethiopia, capacity building focuses on AHRI, in collaboration with an EU sponsored TB-vaccine project TBVAC (www.tb-vac.org). 2) To plan and conduct training-oriented phase-I/IIa TB-vaccine trials in HIV-infected and latently MTB-infected individuals (LTBI) to crystallize clinical R&D capacity building. To develop capacity for conducting trials in Africa we propose a learning-by-doing approach, in which we plan to conduct two phase-I/IIa trials with a leading new TB subunit vaccine. Currently, this new TB-vaccine is being tested in phase-I/IIa (safety/immunogenicity) trials in HIV-seronegative and PPD skin test-negative healthy volunteers in NL (LUMC, 2005/6) and Ethiopia (AHRI, 2006/7), sponsored by TB-VAC (outside APRIOR). These trials need to be followed as soon as possible by phase-I/IIa trials in (1) HIV-seropositive and (2) LTBI-individuals (individuals with a positive PPD-skin test and/or ESAT6/CFP10 blood test (see aim 3)). According to FDA- and EMEA-policies, however, new TB-vaccines must be tested in phase-I trials in a developed country before further testing in developing countries. To meet these criteria, we plan two follow-up trials in Leiden in HIV-seropositive and LTBI-individuals for which we will seek funding elsewhere (TB-VAC or Aeras-Foundation) in case APRIORI is granted. These two trials will embody significant north-south training of African researchers in NL. Subsequently, two APRIORI-sponsored trials will be conducted in Ethiopia in HIV-seropositive and LTB Iindividuals, with a strong south-south capacity building approach, in which Ethiopian researchers will train Tanzanian researchers. LUMC and AHRI will use their expertise to help building capacity for conducting trials KCRC. 3) To build capacity to implement immunological monitoring at the KCMC Biotechnology Laboratory (BTL), to: (a) help diagnosing (latent) MTB infection, particularly in HIV-infected individuals to be included in trials; (b) evaluate vaccine immunogenicity in vaccine trials, and (c) assess efficacy of other (future and APRIORI) TB-interventions such as drug trials, by measuring immune correlates as proxies of bacterial load. We will implement new technologies for immunological monitoring, using validated assays such as QuantiFERON-TB-Gold test and MTB-specific antigen (ESAT6/CFP10) based Elispot tests at KCMC-BTL. These tests will help diagnosing LTBI, needed for selection of participants for clinical trials, including TB-vaccine trials. Tanzania has high rates of LTBI, particularly among HIV-infected subjects (CID 40:1500-1507, 2005), with elevated blood responses to ESAT6. The true prevalence of LTBI, however, remains unknown (KNCV). In addition, these technologies will be used to determine vaccine immunogenicity in phase-I/IIa trials. Moreover, quantitative blood-test responses to MTB-specific antigens ESAT6/CFP10 correlate well with MTB load in TB-patients and their contacts (e.g. CID 40:273-278 (2005); Lancet Inf. Dis. 4:761-776 (2004)), and therefore offer new possibilities to measure efficacy of interventions, including TB treatment. QuantiFERON-TB-Gold test and Elispot tests will be implemented at KCMC/BTL, through north-south (LUMC-SSI-KCMC) and south-south (AHRI-KCMC) capacity building. The project builds on existing African-NL-DK partnerships. KCMC and AHRI/ALERT are locally owned and embedded in the national health systems. |
