Strategy And Specific Objectives

To address this Grand Challenge, sophisticated molecular and immunological tools will be applied by the participating laboratories in the USA and Europe to study host and pathogen responses to latent Mtb infection and active disease in individuals from 5 TB-endemic countries across the African continent. The participating researchers from developing countries and field sites are well established and provide excellent know-how and infrastructure to carry out clinical and natural history studies of TB and HIV-1 infection/AIDS, medical interventions and sophisticated laboratory studies. The Consortium combines multiple scientific disciplines: clinical sciences, epidemiology, microbiology, genomics, genetics, and molecular and cellular immunology.  Six Major Activities or Workpackages (WP) will be covered, each with its specific focus and contribution to meet the selected Grand Challenge.

WP1: Profiling Of Pathogen Response – Identification Of Antigen-Specific T Cell Responses

We will perform genome-wide expression profiling of multiple field isolates of Mtb from the African continent using in vitro conditions that mimic different stages of persistent Mtb infection and disease, in addition to profiling of clinical specimens. This will provide a rational basis for selecting MTB antigens that are potentially targeted by the immune system. Subsequently, we will identify and characterize immune parameters of antigen-specific T cell responses for longitudinal studies in Africa.

WP2: Profiling Of Host Response To Infection – Identification Of Host Markers

We will perform genome-wide expression profiling of local and systemic host responses to Mtb infection and active TB disease using clinical specimens of TB patients, latently infected household contacts and controls. Candidate biomarkers will be verified by multiplex analyses and further analyzed for correlations with prevalent lymphocyte populations and functional properties to identify immune parameters for studies in the field.

WP3: Natural Protective Immunity Against TB

Development of natural protective immunity will be evaluated during follow up of household contacts with recent Mtb infection. We will recruit prospective cohorts of HIV-1 seronegative individuals at 4 African sites and follow them for 2 years to monitor TB disease progression. Longitudinal analyses will include antigen-specific T cell responses and expression of host biomarkers in order to define biomarkers of natural protective immunity and of TB disease.

WP4: Impact Of HIV-1 Infection/Aids And Response To Treatment

To assess the impact of progressive HIV-1 infection on immunity against Mtb, including the effect of antiretroviral treatment, we will recruit prospective cohorts of HIV-1 seropositive individuals at 5 African sites and prospectively follow them for 2 years to monitor acquisition or progression of Mtb infection. Patients on anti-retroviral therapy will be monitored for the development of immune reconstitution syndromes. Longitudinal analyses will be performed of antigen-specific T cell responses and expression of biomarkers in the context of HIV-1 infection in order to refine the set of biomarkers for TB.

WP5: Protective Immunity Following Vaccination With Bcg And Novel TB Vaccine Candidates

We will recruit and follow infants and adolescents who will be vaccinated with BCG. We will monitor the induction of immune responses against mycobacterial antigens and changes in expression levels of biomarkers and correlate these data with the level of protective immunity that is achieved by BCG. In addition, we will exploit the opportunity to test the biomarkers in interlocking studies with new TB vaccine candidates that are scheduled to take place in The Gambia, Ethiopia and South Africa.

WP6: Management And Coordination Of Project, Central Tasks And Reserves

We will ensure effective management of the project, including regular scientific exchange and financial reporting, management of Intellectual Property and ethical affairs. We will facilitate efficient communication and collaborations between the participating sites; foster capacity building, technology transfer and harmonization of clinical protocols, data management and laboratory assays.

Read more: Accomplishments