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

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Bringing antiretroviral drugs to children

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

The challenge

Diarrhoeal diseases account for one in ten deaths of children in sub-Saharan Africa. In 2015, enterotoxigenic E. coli (ETEC) was responsible for an estimated 21,000 deaths in the region (59% of global deaths). In some African countries, ETEC is responsible for more than 10% of deaths from diarrhoeal disease.

Furthermore, although deaths from diarrhoeal diseases have been falling markedly, the incidence of diarrhoeal diseases has not fallen as much. Repeated episodes of diarrhoea increase the risk of death from other infections, and also have a long-term impact on the growth and development of children, affecting their education and later earning potential, as well as their susceptibility to non-communicable diseases in later life.

The ETEC ETVAX study aims to extend use of a highly promising ETEC vaccine, known as ETVAX, to children. ETVAX is a preparation derived from ETEC bacteria that have been engineered to produce high levels of proteins that enable the bacterium to invade the body as well as a hybrid protein based on cholera and ETEC toxins. Delivered with an adjuvant known as dmLT, ETVAX stimulates powerful immune responses against ETEC and is expected to provide protection against 80–85% of ETEC strains in Africa. ETVAX is the only ETEC vaccine in late-stage clinical trials.

ETVAX is being evaluated in phase I and IIb clinical trials (including trials in The Gambia and Zambia supported by the EDCTP). A recent clinical study in Bangladesh has confirmed its safety and immunogenicity in young children, supporting further efficacy trials in this age group. The ETEC ETVAX study is developing a new formulation better suited to young children as well as a user-friendly tool for administering the vaccine. The new all-in-one formulation will then be tested in a phase III trial in Zambia in infants 6–22 months in age.

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.

The ETEC ETVAX study could extend the benefits of ETVAX to young children. As well as its immediate impact on child mortality, ETVAX could also reduce the number of episodes of diarrhoeal disease at a key stage in life, with long-term benefits for health, development, education and economic productivity.

The project aims to generate evidence to support WHO prequalification of an affordable and simple-to-use formulation against a major public health threat in sub-Saharan Africa. It will also strengthen clinical trial and laboratory capabilities in Zambia, particularly expertise in new microbiological and immunological techniques.

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