The MTBVAC-Newborns study will determine whether a weakened form of the TB bacterium is suitable for large-scale trials – potentially offering a better alternative to BCG.

Better TB protection for newborns

BCG (Bacillus Calmette-Guérin) has been used to protect newborn infants against TB for nearly 100 years. It is a weakened (attenuated) form of the bacterium that causes TB in cattle, Mycobacterium bovis. It was developed by repeated culturing of M. bovis and selection for strains that stimulated anti-TB immune responses but did not cause disease.

Although BCG offers generally good protection to newborn infants, it has many drawbacks and is significantly less effective in older age groups. In part, this reflects the fact that attenuation led to the loss not just of genes that trigger disease but also of others that stimulate strong immune responses. Using this knowledge, the MTBVAC team has developed a new vaccine based on M. tuberculosis which has been precisely engineered to eliminate genes central to disease while maintaining those lost in BCG that provoke strong immune responses.

The challenge

MTBVAC has been shown to be safe in healthy adult volunteers and in a small number of newborn infants in South Africa; it appears to stimulate an immune response as least as strong as BCG. In a new trial, the MTBVAC team is carrying out a larger trial in newborn infants in South Africa to evaluate the safety of increasing doses of MTBVAC and the strength of anti-TB immune responses, in comparison with BCG. In parallel, the consortium is building capacity for future large-scale trials in Senegal and Madagascar, which have a high burden of TB.

The project

In theory, MTBVAC should provide better protection in older age groups, but it is also important to determine whether it is a suitable alternative to BCG. Positive results would pave the way to a pivotal phase III trial that would provide definitive evidence of MTBVAC’s efficacy in newborn infants compared with BCG.

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

BCG (Bacillus Calmette-Guérin) has been used to protect newborn infants against TB for nearly 100 years. It is a weakened (attenuated) form of the bacterium that causes TB in cattle, Mycobacterium bovis. It was developed by repeated culturing of M. bovis and selection for strains that stimulated anti-TB immune responses but did not cause disease.

Although BCG offers generally good protection to newborn infants, it has many drawbacks and is significantly less effective in older age groups. In part, this reflects the fact that attenuation led to the loss not just of genes that trigger disease but also of others that stimulate strong immune responses. Using this knowledge, the MTBVAC team has developed a new vaccine based on M. tuberculosis which has been precisely engineered to eliminate genes central to disease while maintaining those lost in BCG that provoke strong immune responses.

MTBVAC has been shown to be safe in healthy adult volunteers and in a small number of newborn infants in South Africa; it appears to stimulate an immune response as least as strong as BCG. In a new trial, the MTBVAC team is carrying out a larger trial in newborn infants in South Africa to evaluate the safety of increasing doses of MTBVAC and the strength of anti-TB immune responses, in comparison with BCG. In parallel, the consortium is building capacity for future large-scale trials in Senegal and Madagascar, which have a high burden of 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.

In theory, MTBVAC should provide better protection in older age groups, but it is also important to determine whether it is a suitable alternative to BCG. Positive results would pave the way to a pivotal phase III trial that would provide definitive evidence of MTBVAC’s efficacy in newborn infants compared with BCG.

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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