Validation of ultrasound bioimaging to predict worm burden and treatment efficacy in preclinical filariasis drug screening models

Abstract

Filariasis is a global health problem targeted for elimination. Curative drugs (macroflaricides) are required to accelerate elimination. Candidate macroflaricides require testing in preclinical models of flariasis. The incidence of infection failures and high intra-group variation means that large group sizes are required for drug testing. Further, a lack of accurate, quantitative adult biomarkers results in protracted timeframes or multiple groups for endpoint analyses. Here we evaluate intra-vital ultrasonography (USG) to identify B. malayi in the peritonea of gerbils and CB.17 SCID mice and assess prognostic value in determining drug efcacy. USG operators, blinded to infection status, could detect intra-peritoneal flarial dance sign (ipFDS) with 100% specifcity and sensitivity, when >5 B. malayi worms were present in SCID mice. USG ipFDS was predictive of macroflaricidal activity in randomized, blinded studies comparing fubendazole, albendazole and vehicle-treated SCID mice. Semi-quantifcation of ipFDS could predict worm burden >10 with 87–100% accuracy in SCID mice or gerbils. We estimate that pre-assessment of worm burden by USG could reduce intra-group variation, obviate the need for surgical implantations in gerbils, and reduce total SCID mouse use by 40%. Thus, implementation of USG may reduce animal use, refne endpoints and negate invasive techniques for assessing anti-flarial drug efcacy.