Stellenbosch University Immunology Research Group
TB Biomarkers and Diagnostics
Immune-endocrine interactions during TB infection and disease
TB Vaccine Trial
The worldwide epidemic of Tuberculosis (TB) requires major interventions on many levels if we are to control its spread and influence on quality and duration of life of those with disease.
Improved diagnostic tests of TB infection and disease, as well as an effective vaccine are some of the interventions that will help in this quest.
The pathogenesis of TB leads to a few host conditions that, rather than being distinct states, occur along a continuum, from exposed, uninfected to sub-clinically infected, to diseased. This continuum extends beyond the treatment phase where differential outcomes occur, including failed treatment, relapse after initial cure and relapse free cure. Reinfection may also occur.
The Stellenbosch University Immunology Research Ggoup is contributing on the basic science level, mainly focusing on biomarker discovery.
A biomarker is a characteristic that can be objectively measured for a person to indicate some biological process, whether normal, pathogenic or a response to treatment for example. Potential TB biomarkers should differentiate between latent and active TB, change with effective therapy and predict treatment outcomes in varied populations, as well as predict vaccine efficacy.
We are involved in several long-term follow-up studies at all the intersections of the TB spectrum.
Biomarkers of Protective Immunity
Household contacts of patients with active TB are a useful group to study for discovering factors that predispose to becoming TB infected after exposure and also to develop disease after having been infected. Only 10% of the TB infected become diseased.
Antigen-specific T cell responses and expression of various cytokines (amongst others) from a large cohort of household contacts of active TB cases have been followed up for two years. These are being studied to find biomarkers that distinguish those who become ill from those who seem to have a natural protective immunity.
Diagnostic markers for latent TB infection
One serious limitation of current diagnostics for latent TB infection (sub-clinical TB) is the inability of tests to differentiate between recent and remote infection. This is important as the risk for progression is highest in the first year after infection. Tests also do not differentiate between the presence of live bacteria and immune memory in the absence live bacteria. We are investigating responses other than Interferon Gamma production to address these limitations.
Diagnostic markers for active TB disease
Even though TB diagnostics have seen significant developments over the last decade, many challenges remain. We contribute to improvements in this field by striving to develop a rapid point of care test for TB, utilizing lateral flow technology recognizing cytokine signatures in whole blood.
Markers for Treatment Response, Cure, Failure and Relapse
Currently early TB treatment response is mainly evaluated by Week 8 sputum conversion and the clinical state of the patient. This is not always adequate. We have recent evidence on end of treatment PET/CT scans that not all patients who are clinically and microbiologically cured according to the National TB program, are in fact free of pulmonary inflammation. Biomarkers of treatment response and risk of treatment failure or TB recurrence/relapse are needed to distinguish patients who are truly cured at end of treatment from those who actually failed treatment or are at risk of relapse.
PET/CT is one such biomarker that we are investigating in a few projects and it shows potential to be used in specific research settings to act as biomarker of treatment response and failure/ recurrence. Other potential candidates are cell surface markers and cytokines.
A study in collaboration with BECTON DICKINSON AND COMPANY, analysed blood samples from patients on TB treatment, to identify the regulation of several surface markers expressed on peripheral blood cells by BD FACSCAP technology flow cytometry.
The Interplay between the Endocrine and the Immune System during TB Infection
There is increasing evidence that the immune system and the endocrine system influence each other. Cytokines produced during an immune response feed back to the hypothalamus and alter the secretion of hormones such as those involved in the hypothalamic-pituitary-adrenal and the hypothalamus-pituitary-gonadal axes. In turn, steroid hormones as well as metabolic hormones, are able to bind to their respective receptors on immune cells and affect the secretion of cytokines and chemokines. We are studying how TB influences the hormonal balance, and are trying to identify the underlying molecular mechanisms of the interplay between the immune and endocrine systems.
The Endocrine dysregulation during type 2 diabetes and risk for TB.
An emerging challenge for TB control is the steadily rising number of individuals with type 2 diabetes (DM2), particularly in developing countries where TB is endemic. DM2 increases the risk of TB by three fold and there are now more people affected by TB-DM co-morbidity than TB-HIV co-infection. A better understanding of the link between TB and DM2 is essential to identify individuals at increased risk for TB progression. Dr Ronacher has just received a five year NIH RO1 grant (2015-2020) to investigate whether the endocrine dysregulation during type 2 diabetes (DM2) contributes to impaired immune responses and reduced bacterial killing during infection with
Mycobacterium tuberculosis / HIV co-infection.
The Impact of Contraceptives on Immune Responses to TB Infection
Medroxyprogesterone aceate (MPA), also known as Depo Provera is the most commonly used contraceptive in South Africa and other developing countries. Unlike other synthetic progestins, MPA possesses selective glucocorticoid activity and it is well known that glucocorticoids cause reactivation of latent TB. Given that over 60% of women using contraceptives choose MPA in our study cohort, where the TB incidence is 948/100 000, we are investigating the impact of MPA use on immune responses to TB. Ultimately we would like to elucidate whether MPA, compared to other contraceptives, affects susceptibility to TB, disease severity or response to TB treatment.
The group is actively involved in TB vaccine research. The main focus of our participation revolves around the exploratory immunological laboratory analysis of the TB vaccines. It is important for us to understand the complexity of the immune responses induced by the different vaccines. Here we evaluate the phenotype and multi-functionality of cells induced by vaccination. We have been involved in several trials ranging from booster vaccines to potential BCG replacements. The latest of the trials is in collaboration with Vakzine Projekt Management GmbH, a German vaccine company. We are the lead immunological facility for a trial with several partners. We are also working in close collaboration with the South African Vaccine Initiative (SATVI) in an attempt to harmonize and standardize assays used for vaccine analysis. Members from our group are also actively involved with the Tuberculosis Vaccine Initiative (TBVI) based in The Netherlands to facilitate the development of new vaccines.
Past and present vaccine trials done by SUNIRG:
VPM1002-ZA-2.13TB (phase IIb) trial
ID93 (IDRI-TBVPX-20) phase II (in collaboration with IDRI)
VPM1002-ZA-2.12TB (phase IIa) trial
VPM1002-ZA-1.10TB (phase Ib)
IMPAACT1073 (HIV-IRIS trial) in collaboration with SATVI
IMPAACTP1041 (Randomized double blind, placebo controlled trial to determine the efficacy of INH) in collaboration with Prof Mark Cotton (KidCru)
The Stellenbsoch University Immunology Research Group has recently appointed two dedicated senior bioinfomaticians to establish a bioinfomatics unit at our faculty. This will greatly increase our capacity to harness the large amounts of immunological and genetic information that TB studies are generating, and will serve the TB biomarker community in an institutionally independent manner. We are part of international and local research collaborations that aim to promote biomarker bioinformatics as a means to find answers for many of the key questions in tuberculosis immunology.
»Read more about our bioinformatics here.