LYMPHATIC FILARIASIS
BACKGROUND
Lymphatic filariasis (LF), also known as elephantiasis, is a painful, debilitating disease characterized by severe swelling in the arms, legs, breasts, or genitals. Affected people are often rejected by others because of their disfigurement and disability. LF is caused by infection with parasites classified as nematodes (roundworms) of the family Filariodidea. There are 3 types of these thread-like filarial worms:
Wuchereria bancrofti, which is responsible for 90% of worldwide cases (“Bancroftian LF”) and is found throughout Sub-Saharan Africa, in several Western Pacific Island nations and territories, and parts of the Caribbean. It also occurs sporadically in South America, India, and Southeast Asia.
Brugia malayi, which causes most of the remainder of the cases (“Brugian LF”) and is primarily found in South and Southeast Asia
Brugia timori, which also causes the disease but has a very limited geographic distribution, being found exclusively in the eastern islands of the Lesser Sunda archipelago in Indonesia, including Timor-Leste.
Funding by USAID and the Gates Foundation allowed our partners at Drugs & Diagnostics for Tropical Diseases (DDTD) to develop excellent prototype tests for both Bancroftian and Brugian LF, which were subsequently in-licensed by Big Eye Diagnostics and are currently being progressed on the road to commercialization.
A NEW RAPID TEST FOR BANCROFTIAN LF
Two field-deployable tests designed to detect circulating filarial antigen (CFA) from adult W. bancrofti worms, the Immunochromatography Test Card (ICT) and the Filariasis Test Strip (FTS), were used for more than two decades to detect active infections. However, antigen tests may not be optimally suited for post-MDA surveillance activities, as they detect the disease only 18 months after a person has been infected and, in addition, lack sensitivity in post-MDA settings due to the low parasite burden in individuals having previously undergone drug treatment. Serological tests, which do not directly detect W. bancrofti antigens but rather IgG4 antibodies raised by the human host against these antigens, have been developed and used in both laboratory-based Enzyme-Linked Immunosorbent Assays (ELISAs) and in the only commercial, field-deployable RDT, the SD Bioline Lymphatic Filariasis IgG4 Test. All currently available serological tests are designed in such a way as to detect human IgG4 antibodies against the archetypical W. bancrofti antigen, Wb123, discovered by the group of Dr. T. Nutman at the National Institute for Allergy and Infectious Diseases (NIAID). None of the field-deployable tests mentioned above meets the criteria defined by the TPP for LF surveillance.
We have succeeded in developing a highly sensitive second-generation Wb123 test which meets, or comes at lease close to meeting, all key TPP criteria, particularly in terms of sensitivity (> 85%) and specificity (> 98.8%). We are also evaluating the potential of adding a second antigen to further increase specificity. Our new test is being progressed to manufacturing process development under an NIH SBIR Phase I/II Fast-Track grant, with the goal to enter regulatory review by WHO’s Expert Review Panel for Diagnostics (ERPD) in 2026.
A NEW RAPID TEST FOR BRUGIAN LF: THE BRUGIA TEST PLUS (BT+)
The gold standard methods for diagnosing infection by Brugia species include examination of nighttime blood by microscopy or PCR for the presence of embryos (microfilariae) in the bloodstream. This is logistically too complicated and costly for programmatic use in TAS. ELISA formats exist but remain confined to laboratory use. The best practice recommended by WHO for transmission assessment surveys (TAS) has long been the use of the only commercial serological RDT, the Brugia Rapid Test (BRT). However, some quality issues have been encountered with the BRT over the years leading some Brugia programs to be paused. A new RDT that meets the TPP and is manufactured under a stringent quality assurance program is critically needed today to resume programs for Brugian LF. Against this backdrop, our partners at Drugs & Diagnostics for Tropical Diseases (DDTD) received funding from the Gates Foundation to develop a new prototype test for Brugian LF with improved characteristics. The resulting new test, termed Brugia Test Plus (BT+), was independently evaluated at Universiti Sains Malaysia (USM) and at Washington University in St. Louis (WUSTL), as well as in two field studies in Belitung East (Indonesia) and Sabah (Malaysia), and shown to satisfy all key criteria of the WHO Target Product Profile for LF Surveillance. BT+ performed well and reproducibly in high-temperature and high-humidity conditions and received very positive end user feedback.
Big Eye Diagnostics in-licensed BT+ from DDTD in 2024 and subsequently managed to produce a further optimized, design-locked candidate test under an NIH SBIR Direct-to-Phase II grant. In July 2024, the LF Subgroup of the WHO Diagnostic Technical Advisory Group (DTAG) recommended BT+ for future use in surveys and in early 2025, WHO ordered 65’000 test to support programs in Indonesia and India. With BT+ thus on the verge of programmatic adoption by WHO, we are currently developing an automated high-throughput manufacturing process in compliance with ISO-13485:2016 quality standards.