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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

BCG is used in many countries to prevent TB infections in children. However, there is some evidence that BCG has more general stimulatory effects on the immune system and enhances protection against other infections.

Furthermore, preliminary analyses suggest that countries with routine BCG vaccine programmes have been less badly affected by COVID-19. However, the evidence is not yet strong enough for BCG to be recommended as a preventive intervention for COVID-19.

The RE-BCG-CoV-19 project aims to determine whether BCG revaccination of front-line health workers in South Africa, who are at significant risk of acquiring SARS-CoV-2 infections, prevents infection or reduces the severity of symptoms.

The project is conducting a placebo-controlled trial (NCT04379336) involving at least 500 healthcare workers at clinical sites in South Africa. Participants will be followed up for a year, during which they will be regularly tested for SARS-CoV-2 infection, and their general health will also be monitored. Impacts on TB acquisition will also be assessed, as well as the effects of latent TB infections on COVID-19-related morbidity and mortality.

Regular interim data assessments will be undertaken, with data reviewed by an independent data safety and monitoring board. If early signs are detected that BCG revaccination is proving protective, it will therefore be possible to rapidly roll out vaccination more widely.  The trial protocol is aligned with studies conducted in Europe and elsewhere to make it possible for later meta-analyses of pooled results.

Complementing this clinical study, the project team is also planning to use a novel ‘organoid’ model to explore the cascade of events following SARS-CoV-2 infection. Organoids are complex three-dimensional cellular assemblages that can be grown in culture and form structures resembling human lung tissue. As they include cells of the immune system, they can be used to track immune responses following SARS-CoV-2 infection of lung epithelial cells, which will help to identify responses associated with control of virus replication. The model will also provide a way to assess the impact of BCG vaccination on SARS-CoV-2 infection and viral replication, and shed light on the immune mechanisms underlying any protective effect.

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.

BCG has been used since the 1920s to protect against TB disease. It is safe, affordable and widely available. Therefore, if the RE-BCG-CoV-19 project identifies a protective effect, it could be rapidly introduced to mitigate the impact of COVID-19. RE-BCG-CoV-19 project data will complement other studies being carried out on BCG, contributing data specific to an African population. In addition, the laboratory studies will provide important insight into mechanisms of protection, to inform the development of other interventions.

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