“
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.

The challenge

Ebola and Marburg viruses (EBOV and MARV) form the two generic members of the filoviridae family of viruses. Filoviruses cause rare but highly fatal viral hemorrhagic fevers (VHFs) within rural villages of equatorial Africa. The 2014-2015 Ebola outbreak in West Africa turned into a public health emergency of international concern (PHEIC). Filoviruses are class A pathogens of potential bioterror. There are no easy to use, affordable rapid diagnostic tests for early detection of filoviruses at the point of care (POC) yet.

In January 2013, Grand Challenges Canada (through its rising Stars in Global Health scheme) funded Dr Wayengera and his team to test novel conserved epitopes of EBOV/MARV glycoprotein (Gp) as potential diagnostic biomarkers (Grant #S4-0280-01). During the 2014 to 2015 outbreak in West Africa, we transitioned to scale. Over this period, we generated and validated a panel of over 12 mice-derived hybridomas and monoclonal antibodies (MAbs- targeting 4 unique epitopes inclusive of the extracellular domain of EBOV/MARV Gp) for their reactivity with recombinant Gp cloned and expressed within HEK mammalian cells.

The overall goal of this fellowship project is to determine receiver operator characteristics of novel EBOV/MARVGP epitopes using Sierra Leonean patient-samples obtained from the 2014-2015 Ebola outbreak, stored at the National Institute for Communicable Diseases (NICD) Center for Emerging Zoonotic Diseases (CEZD) BSL-IV. Two specific aims are contingent on this goal, i.e to 1) Pre-characterise the patient sample by clinical picture and outcome, ELISA, RT-PCR, and viral culture, and 2) Determine the sensitivity, specificity, positive predictive value, negative predictive value and receiver operator curves of our in vitro pre-validated novel epitopes.

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.

These conserved EBOV/MARV-Gp epitopes and their derivative MAbs are potential biomarkers to mount on a lateral flow immunochromatographic strip-test (LFT) for use at a point of care, e.g. in remote village settings of equatorial Africa, or during a bioterror attack.

The team has initiated testing at the NICDCEZD-BSL-IV in collaboration with LifeAssay Diagnostics but will require more funding to reproduce high-affinity purified MAbs for clinical testing. In addition, the fellow will train 2 Master’s students in Laboratory Practice and Standards.

In August 2019, Dr Wayengera received for his research the first prize in the competition for the WHO Innovation Challenge in the category Product development.

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