The POR TB trial is evaluating a novel strategy for protecting against TB – preventing latent infections from springing back to life.

A new approach for TB vaccination

Most TB vaccines aim to prevent new infections. However, an estimated 2 billion people are already infected with Mycobacterium tuberculosis. Although 1.5 million lives are lost to TB every year, not everyone with an M. tuberculosis infection develops clinical disease. Hence an alternative goal for vaccination is to promote immune responses that keep an existing infection in check – which is likely to require a different type of vaccine from one designed to prevent initial infection.

The POR TB team has developed a candidate vaccine, known as H56:IC31, that has been specifically designed to protect people already exposed to M. tuberculosis. It is based on a fusion protein (known as H56) containing antigens made by M. tuberculosis at different stages of its life cycle, combined with an adjuvant (IC31). Preliminary clinical trials have shown that H56:IC31 is safe and stimulates good immune responses of the kind thought likely to be protective.

The challenge

The POR TB consortium is now carrying out a larger phase II trial, to assess the safety and efficacy of H56:IC31 using a ‘prevention of recurrence’ approach not previously applied to TB. Even after successful treatment of TB, up to 10% of patients experience a relapse – their TB returns, following reinfection or reawakening of dormant bacteria that survived initial treatments. Preventing recurrence would improve the success of treatments and reduce the spread of TB.

In the placebo-controlled POR TB trial, H56:IC31 will be given to TB patients who have successfully completed 6 months of standard TB treatment. Patients will be monitored for 2 years for recurrence of their TB.

The project

Complementing preventive vaccines such as BCG, H56:IC31 could enhance the long-term success rates of TB drug treatments. Potentially, by stimulating host responses to infection, it could also provide a route to shortened drug treatments.

The POR TB consortium is also piloting a novel clinical trial approach and measures of success that could be adopted for evaluation of similar products. Finally, the trial will also generate data on the elements of the immune response and features of M. tuberculosis that are associated with recurrence or the success of vaccination to prevent recurrence.

Impact


crucial in

widening African

children’s access

to antiretrovirals

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

Most TB vaccines aim to prevent new infections. However, an estimated 2 billion people are already infected with Mycobacterium tuberculosis. Although 1.5 million lives are lost to TB every year, not everyone with an M. tuberculosis infection develops clinical disease. Hence an alternative goal for vaccination is to promote immune responses that keep an existing infection in check – which is likely to require a different type of vaccine from one designed to prevent initial infection.

The POR TB team has developed a candidate vaccine, known as H56:IC31, that has been specifically designed to protect people already exposed to M. tuberculosis. It is based on a fusion protein (known as H56) containing antigens made by M. tuberculosis at different stages of its life cycle, combined with an adjuvant (IC31). Preliminary clinical trials have shown that H56:IC31 is safe and stimulates good immune responses of the kind thought likely to be protective.

The POR TB consortium is now carrying out a larger phase II trial, to assess the safety and efficacy of H56:IC31 using a ‘prevention of recurrence’ approach not previously applied to TB. Even after successful treatment of TB, up to 10% of patients experience a relapse – their TB returns, following reinfection or reawakening of dormant bacteria that survived initial treatments. Preventing recurrence would improve the success of treatments and reduce the spread of TB.

In the placebo-controlled POR TB trial, H56:IC31 will be given to TB patients who have successfully completed 6 months of standard TB treatment. Patients will be monitored for 2 years for recurrence of their TB.

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.

Complementing preventive vaccines such as BCG, H56:IC31 could enhance the long-term success rates of TB drug treatments. Potentially, by stimulating host responses to infection, it could also provide a route to shortened drug treatments.

The POR TB consortium is also piloting a novel clinical trial approach and measures of success that could be adopted for evaluation of similar products. Finally, the trial will also generate data on the elements of the immune response and features of M. tuberculosis that are associated with recurrence or the success of vaccination to prevent recurrence.

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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