EDCTP portfolio: Career Development Fellowships

Dr Jason Limberis aims to validate a biosignature of infectiousness in cough aerosol samples for identification of patients with active TB.

Quickly finding highly infectious TB patients

Tuberculosis remains the top infectious disease killer globally. TB is primarily an airborne disease transmitted by inhaling infectious cough aerosol particles <10microns containing live Mycobacterium tuberculosis bacilli. Wide heterogeneity exists in patients’ ability to aerosolise and transmit M. tuberculosis (infectiousness). However, the reasons for this remain poorly understood.

Unravelling the fundamental biology of infectiousness is critical to understand transmission and to develop interventional strategies. A major hurdle is that existing tests to measure infectiousness, i.e. guinea pig models and cough aerosol sampling technology (CASS), are expensive, technically difficult, take more than six weeks to generate results, and are not scalable. Thus, scalable biomarkers are urgently required to identify highly infectious patients and to rapidly identify those with highly drug-resistant TB for targeted interventions.

The challenge

In the CASS I study, 453 TB patients were investigated using novel CASS that can enumerate the inhalable <10micron infectious particles that initiate disease. A preliminary set of clinical and microbiological characteristics was defined that can identify infectious patients with ~80% accuracy using CASS as a reference standard in a biorepository of 453 patient-derived samples. Interestingly, no significant M. tuberculosis-specific mutations were detected in those  who were CASS+ve (infectious) versus CASS-ve (non-infectious).

Dr Limberis hypothesises that patients with culturable M. tuberculosis bacilli in their cough aerosol have a different clinical and transcriptomic profile (multidimensional biosignature of clinical and microbiological characteristics, and host and M. tuberculosis transcriptomes) than patients who do not. The overarching aim of the CASS II study is to develop and validate this multidimensional combinatorial biosignature in patients who have culturable M. tuberculosis in their cough aerosol, as compared to those who do not (CASS+ve versus CASS-ve).

RNA sequencing will be performed and analysis conducted on 200 sputum and blood sample sets from our biorepository of CASS+ve and CASS-ve patients (100 in each group). Further, machine learning approaches will be used to identify and validate a multidimensional biosignature (clinical and transcriptomic variables) of infectiousness using CASS positivity as a reference.

The project

This project will shed light on the fundamental biology of TB transmission and potentially uncover therapeutic or vaccine targets to interrupt disease spread. Furthermore, a biosignature of infectiousness will allow for the targeting of infectious individuals with extensively drug-resistant and incurable TB (now a major problem in endemic countries), helping to limit the spread of this deadly disease.

Impact


test the safety and efficacy of this new formulation in young children

Bringing antiretroviral drugs to children

The CHAPAS trials have ensured that many more children with HIV have benefited
from life-saving antiretrovirals.

EDCTP portfolio: HIV & HIV-associated infections

The challenge

Tuberculosis remains the top infectious disease killer globally. TB is primarily an airborne disease transmitted by inhaling infectious cough aerosol particles <10microns containing live Mycobacterium tuberculosis bacilli. Wide heterogeneity exists in patients’ ability to aerosolise and transmit M. tuberculosis (infectiousness). However, the reasons for this remain poorly understood.

Unravelling the fundamental biology of infectiousness is critical to understand transmission and to develop interventional strategies. A major hurdle is that existing tests to measure infectiousness, i.e. guinea pig models and cough aerosol sampling technology (CASS), are expensive, technically difficult, take more than six weeks to generate results, and are not scalable. Thus, scalable biomarkers are urgently required to identify highly infectious patients and to rapidly identify those with highly drug-resistant TB for targeted interventions.

In the CASS I study, 453 TB patients were investigated using novel CASS that can enumerate the inhalable <10micron infectious particles that initiate disease. A preliminary set of clinical and microbiological characteristics was defined that can identify infectious patients with ~80% accuracy using CASS as a reference standard in a biorepository of 453 patient-derived samples. Interestingly, no significant M. tuberculosis-specific mutations were detected in those  who were CASS+ve (infectious) versus CASS-ve (non-infectious).

Dr Limberis hypothesises that patients with culturable M. tuberculosis bacilli in their cough aerosol have a different clinical and transcriptomic profile (multidimensional biosignature of clinical and microbiological characteristics, and host and M. tuberculosis transcriptomes) than patients who do not. The overarching aim of the CASS II study is to develop and validate this multidimensional combinatorial biosignature in patients who have culturable M. tuberculosis in their cough aerosol, as compared to those who do not (CASS+ve versus CASS-ve).

RNA sequencing will be performed and analysis conducted on 200 sputum and blood sample sets from our biorepository of CASS+ve and CASS-ve patients (100 in each group). Further, machine learning approaches will be used to identify and validate a multidimensional biosignature (clinical and transcriptomic variables) of infectiousness using CASS positivity as a reference.

The project

The later CHAPAS-3 trial compared the efficacy and safety of three fixed-dose combinations including two without stavudine (found to have some long-term side effects in adults, leading to a recommendation that its use be discontinued in children). The trial the first of its kind in Africa studied nearly 500 children at four sites in two African countries.

This project will shed light on the fundamental biology of TB transmission and potentially uncover therapeutic or vaccine targets to interrupt disease spread. Furthermore, a biosignature of infectiousness will allow for the targeting of infectious individuals with extensively drug-resistant and incurable TB (now a major problem in endemic countries), helping to limit the spread of this deadly disease.

ratios forfixed-dose combinations and on appropriatedosage according to weight. 

The CHAPAS-3 trial confirmed the effectiveness of fixed-dose combinations, providing further impetus to the rollout of antiretrovirals to children. Its evidence on abacavir informed the WHO recommendation of abacavir-containing combinations for first-line therapy in children. Trial data have also been used to support applications for regulatory approval for new scored efavirenz tablets.

Impact

L’homme RF et al. Nevirapine, stavudine and lamivudine pharmacokinetics in African children on paediatric fixed-dose combination tablets. AIDS. 2008;22(5):557–65.

Mulenga V et al. Abacavir, zidovudine, or stavudine as paediatric tablets for African HIVinfected children (CHAPAS-3): an open-label, parallel-group, randomised controlled trial. Lancet Infect Dis. 2016;16(2):169–79.

WHO. Guidelines on the use of antiretroviral drugs for treating and preventing HIV infection: recommendations for a public health approach. 2010.

WHO. Consolidated guidelines on the use of antiretroviral drugs
for treating and preventing

HIV infection: Recommendations for a public health approach
(second edition). 2016

Projects: Children with HIV in Africa Pharmacokinetics and Adherence of Simple Antiretroviral Regimens (CHAPAS): CHAPAS-1 and -3

Project lead: Professor Chifumbe Chintu, University Teaching Hospital, Zambia (CHAPAS-1); Dr Veronica Mulenga, University Teaching Hospital, Zambia (CHAPAS-3)

Target population(s): Children with HIV

Sample size: 71 (CHAPAS-1); 480 (CHAPAS-3)

Countries involved: Ireland, the Netherlands, the UK, the USA, Zambia (CHAPAS-1); Uganda, Zambia (CHAPAS-3)

Project duration: 2005–2009 (CHAPAS-1); 2010 –2011 (CHAPAS-3)

EDCTP funding: €1.2M (CHAPAS-1); €4.6M (CHAPAS-3)

Total project funding: €1.2M (CHAPAS-1); €5.0M

About us

The European & Developing Countries Clinical Trials Partnership (EDCTP) is a public–public partnership between 14 European and 16 African countries, supported by the European Union. EDCTP’s vision is to reduce the individual, social and economic burden of poverty-related infectious diseases by affecting sub-Saharan Africa. EDCTP’s mission is to accelerate the development of new or improved medicinal products for the identification, treatment and prevention of infectious diseases, including emerging and re-emerging diseases, through pre- and postregistration clinical studies, with emphasis on phase II and III clinical trials. Our approach integrates conduct of research with development of African clinical research capacity and networking. The second EDCTP programme is implemented by the EDCTP Association supported under Horizon 2020, the European Union’s Framework Programme for Research and Innovation.

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