Clinical And Therapeutic Studies Of Human Filariasis and Related Diseases

National Institute Of Allergy And Infectious Diseases

Investigators

Linked publications, trials & patents

Abstract

Having developed both molecular and recombinant antigen-based approaches to sensitive and specific diagnosis for filarial and STH infections, we utilized these diagnostics around the world and have provided insights into parasite transmission dynamics in Mali, Southeast Asia (Myanmar/Thailand), Cameroon, and Ecuador. A number of epidemiologic studies have been performed in Mali and Cameroon (see references below) to both demonstrate the efficacy of yearly MDA programs to interrupt transmission of W. bancrofti and O. volvulus and to assess the role of Loa loa in being a barrier to MDA-based elimination programs. In addition, we have demonstrated (likely for the first time in South America) infections in humans by the zoonotic hookworm Ancylostoma ceylanicum and have mapped its distribution throughout Ecuador Helping define the cause of the Nodding Syndrome (NS), a devastating syndrome associated with O. volvulus infection, has been a part of the work of the HIS over the past 10 years. Previously, we helped demonstrate the association of NS with the presence of O. volvulus -specific antibodies and had shown that these antibodies induce an autoreactive neurotoxic response that may be responsible for the syndrome. Over the last 4 years, we have provided additional new insights into these cross-reactive autoantibodies by showing that they are not locally produced in the CNS and that, in a comprehensive family study of an extended kindred performed as part of the Undiagnosed Disease Service at the NIH, was not genetically based. As has been mentioned above, we have used molecular and bioinformatic approaches to identify diagnostic targets for many parasitic infections. Using methodologies to identify highly repetitive DNA short sequences, we have developed new molecular approaches for highly sensitive parasite detection for the major filarial infections (L. loa, W. bancrofti, O. volvulus, and M.perstans), the causative parasite agents of eosinophilic meningitis (A. cantonensis, T. canis/catti, B. pycronis; Gnathostome spp, T. solium) T. cruzi (all serotypes), and most recently all Leishmania spp (Duncan et al, 2025 Clin Infect Dis). Many of these assays can detect the parasite DNA as cell free circulating DNA/RNA (cfcDNA/cfcRNA) in plasma, CSF, and/or urine ( Salazar et al, 2025 J Infect Dis; Bennuru et al, 2025, J Infect Dis) The development of point of contact (POC) isothermal nucleic acid detection methods has been a major effort in the past year. Almost all of the qPCR assays mentioned above have been converted to recombinase polymerase assays (RPA) that can be visually without instrumenation; moreover, we have coupled these to CAS12a methods to improve sensitivity and allow for lateral flow readouts. Highly specific recombinant parasite antigens discovered in the laboratory have been used as the basis for a number of lateral flow assays already in widespread use across the world (e.g. Ov16 and Wb123). Commercialization of an RDT using 2 recombinant S. stercoralis proteins (NIE/Ss-IR) is underway (Sears et al, 2022 PLoS Negl Trop Dis; Lontuo-Fogang et al, 2025 PLoS Negl Trop Dis) as is a new O. volvulus biplex RDT using a second antigen OvOC3261 also discovered in the HIS. A randomized placebo-controlled trial was initiated in two rural health districts in Mali. Patients with lymphedema (LE) were randomized to receive either doxycycline (200 mg/day) or placebo over a 6-week monitored treatment period and were then followed every 6 months for 2 years. Both groups limb hygiene that was carried out daily for the entire 2-year study. In a study population of 200 (100 in each arm), there was no significant difference at month 24 after treatment initiation in the number of subjects showing progression in LE stage between the two treatment arms. Importantly, however, the number of attacks of acute adenolymphangitis (ADLA) was reduced in both arms, Doxycycline was well tolerated in those receiving the drug. When added to daily self-administered limb hygiene, a 6-week course of doxycycline (200 mg) was found to be was not superior to placebo in increasing the improvement associated with hygiene alone in volume, stage, or frequency of ADLA attacks over a 24-month period. A similarly large randomized placebo-controlled study was performed in Uganda to examine the role of doxycycline in the nodding syndrome (NS). In this phase 2 trial, again there was no significant salutary effect of doxycycline in NS