The success of Community Directed Treatment with Ivermectin (CDTI) in the Americas and Africa has led to a target of eliminating infection with Onchocerca volvulus, the filarial nematode that causes onchocerciasis, in 80% of endemic African countries by 2025. This ambitious goal depends on sustaining not only drug coverage but also sustaining drug sensitivity for treatment periods as long as 25 years in hyperendemic foci, and also on preventing post-CDTI recrudescence due to reinvasion of parasites from regions where elimination has not been achieved. These two requirements for successful and sustainable elimination require the development of new tools capable of routine monitoring of ivermectin susceptibility and of modelling parasite migration over several spatial and temporal scales so that the risk of post-CDTI recrudescence can be estimated objectively. We propose to extend our existing data on genetic associations for ivermectin response to develop a panel of genetic markers predictive of that response as the basis for a simple genotyping surveillance tool for ivermectin efficacy, and to extend our existing data on O. volvulus population structure to parameterize a mathematical model of onchocerciasis (EpiOncho) so that recrudescence risk can be estimated quantitatively. We will carry out genotype-by-sequencing and genetic association analysis on >300 adult female worms whose ivermectin response is known then test the ability of the resulting panel of genetic markers to accurately predict repopulation rates in the skin following ivermectin treatment in additional, previously uncharacterized foci elsewhere in Africa. Similarly, we will carry out genotyping-by-sequencing of a large, geographically diverse selection of microfilariae and infective larvae from throughout Africa to develop and test a panel of markers that define the boundaries of parasite transmission zones and can be used to assign parasites to a population of origin. These data will be used to parameterize a ?patch model? version of EpiOncho. The expected outcome will promote development of much needed tools to (i) monitor ivermectin efficacy (ii) estimate risk of post- treatment recrudescence and (iii) facilitate successful elimination of onchocerciasis.
Onchocerciasis is a filarial disease that was, prior to the introduction of ivermectin, considered one of the leading causes of morbidity due to blindness, visual impairment, skin disease and neurological complications and a major constraint on economic development in affected countries. There are an estimated 197 million people at risk of onchocerciasis in Africa. The success of ivermectin and the impact of the disease when not controlled have led to targets for elimination. Elimination, however, requires additional, new tools to safeguard ivermectin efficacy and minimize the risk of post-treatment recrudescence of infection that were not necessary when the target was control as a public health problem. This proposal will provide the basic research on which the development of those new tools for elimination can be based.
