The present document outlines the next steps recommended by the Skin NTDs subgroup of the DTAG to operationalise individual disease TPPs and to advance the NTD road map approach of scaling up integrated approaches to skin NTDs.
Michael Marks, Sundeep Chaitanya Vedithi, Wendy W J van de Sande, Bruno Levecke, Anthony W Solomon, Kingsley Asiedu, Camilla L Ducker, Patrick Lammie, Daniel Argaw Dagne, Isra Cruz; WHO Diagnostic Technical Advisory Group on Neglected Tropical Diseases. PLoS Negl Trop Dis. 2024 Nov 25;18(11):e0012661. doi: 10.1371/journal.pntd.0012661. eCollection 2024 Nov.
Fig 1. Workflow for the selection of the optimal qPCR assay.
Background: Onchocerca volvulus is a filarial parasite that is a major cause of dermatitis and blindness in endemic regions primarily in sub-Saharan Africa. Widespread efforts to control the disease caused by O. volvulus infection (onchocerciasis) began in 1974 and in recent years, following successful elimination of transmission in much of the Americas, the focus of efforts in Africa has moved from control to the more challenging goal of elimination of transmission in all endemic countries. Mass drug administration (MDA) with ivermectin has reached more than 150 million people and elimination of transmission has been confirmed in four South American countries, with at least two African countries having now stopped MDA as they approach verification of elimination. It is essential that accurate data for active transmission are used to assist in making the critical decision to stop MDA, since missing low levels of transmission and infection can lead to continued spread or recrudescence of the disease.
Methodology/principal findings: Current World Health Organization guidelines for MDA stopping decisions and post-treatment surveillance include screening pools of the Simulium blackfly vector for the presence of O. volvulus larvae using a PCR-ELISA-based molecular technique. In this study, we address the potential of an updated, practical, standardized molecular diagnostic tool with increased sensitivity and species-specificity by comparing several candidate qPCR assays. When paired with heat-stable reagents, a qPCR assay with a mitochondrial DNA target (OvND5) was found to be more sensitive and species-specific than an O150 qPCR, which targets a non-protein coding repetitive DNA sequence. The OvND5 assay detected 19/20 pools of 100 blackfly heads spiked with a single L3, compared to 16/20 for the O150 qPCR assay.
Conclusions/significance: Given the improved sensitivity, species-specificity and resistance to PCR inhibitors, we identified OvND5 as the optimal target for field sample detection. All reagents for this assay can be shipped at room temperature with no loss of activity. The qPCR protocol we propose is also simpler, faster, and more cost-effective than the current end-point molecular assays.
Mary Doherty, Jessica R Grant, Nils Pilotte, Sasisekhar Bennuru, Kerstin Fischer, Peter U Fischer, Sara Lustigman, Thomas B Nutman, Kenneth Pfarr, Achim Hoerauf, Thomas R Unnasch, Hassan K Hassan, Samuel Wanji, Patrick J Lammie, Eric Ottesen, Charles Mackenzie, Steven A Williams. PLoS Negl Trop Dis. 2023 Dec 14;17(12):e0011815. doi: 10.1371/journal.pntd.0011815.
Trachoma, caused by ocular Chlamydia trachomatis infection, is targeted for global elimination as a public health problem by 2030. To provide evidence for use of antibodies to monitor C. trachomatis transmission, we collated IgG responses to Pgp3 antigen, PCR positivity, and clinical observations from 19,811 children aged 1-9 years in 14 populations. We demonstrate that age-seroprevalence curves consistently shift along a gradient of transmission intensity: rising steeply in populations with high levels of infection and active trachoma and becoming flat in populations near elimination. Seroprevalence (range: 0-54%) and seroconversion rates (range: 0-15 per 100 person-years) correlate with PCR prevalence (r: 0.87, 95% CI: 0.57, 0.97). A seroprevalence threshold of 13.5% (seroconversion rate 2.75 per 100 person-years) identifies clusters with any PCR-identified infection at high sensitivity ( >90%) and moderate specificity (69-75%). Antibody responses in young children provide a robust, generalizable approach to monitor population progress toward and beyond trachoma elimination.
Christine Tedijanto, Anthony W Solomon, Diana L Martin, Scott D Nash, Jeremy D Keenan, Thomas M Lietman, Patrick J Lammie, Kristen Aiemjoy, Abdou Amza, Solomon Aragie, Ahmed M Arzika, E Kelly Callahan, Sydney Carolan, Adisu Abebe Dawed, E Brook Goodhew, Sarah Gwyn, Jaouad Hammou, Boubacar Kadri, Khumbo Kalua, Ramatou Maliki, Beido Nassirou, Fikre Seife, Zerihun Tadesse, Sheila K West, Dionna M Wittberg, Taye Zeru Tadege, Benjamin F Arnold. Nat Commun. 2023 Jun 5;14(1):3269. doi: 10.1038/s41467-023-38940-5.
Background: Infectious diseases continue to burden populations in Malaysia, especially among rural communities where resources are limited and access to health care is difficult. Current epidemiological trends of several neglected tropical diseases in these populations are at present absent due to the lack of habitual and efficient surveillance. To date, various studies have explored the utility of serological multiplex beads to monitor numerous diseases simultaneously. We therefore applied this platform to assess population level exposure to six infectious diseases in Sabah, Malaysia. Furthermore, we concurrently investigated demographic and spatial risk factors that may be associated with exposure for each disease.
Methods: This study was conducted in four districts of Northern Sabah in Malaysian Borneo, using an environmentally stratified, population-based cross-sectional serological survey targeted to determine risk factors for malaria. Samples were collected between September to December 2015, from 919 villages totaling 10,100 persons. IgG responses to twelve antigens of six diseases (lymphatic filariasis- Bm33, Bm14, BmR1, Wb123; strongyloides- NIE; toxoplasmosis-SAG2A; yaws- Rp17 and TmpA; trachoma- Pgp3, Ct694; and giardiasis- VSP3, VSP5) were measured using serological multiplex bead assays. Eight demographic risk factors and twelve environmental covariates were included in this study to better understand transmission in this community.
Results: Seroprevalence of LF antigens included Bm33 (10.9%), Bm14+ BmR1 (3.5%), and Wb123 (1.7%). Seroprevalence of Strongyloides antigen NIE was 16.8%, for Toxoplasma antigen SAG2A was 29.9%, and Giardia antigens GVSP3 + GVSP5 was 23.2%. Seroprevalence estimates for yaws Rp17 was 4.91%, for TmpA was 4.81%, and for combined seropositivity to both antigens was 1.2%. Seroprevalence estimates for trachoma Pgp3 + Ct694 were 4.5%. Age was a significant risk factors consistent among all antigens assessed, while other risk factors varied among the different antigens. Spatial heterogeneity of seroprevalence was observed more prominently in lymphatic filariasis and toxoplasmosis.
Conclusions: Multiplex bead assays can be used to assess serological responses to numerous pathogens simultaneously to support infectious disease surveillance in rural communities, especially where prevalences estimates are lacking for neglected tropical diseases. Demographic and spatial data collected alongside serosurveys can prove useful in identifying risk factors associated with exposure and geographic distribution of transmission.
YuYen L Chan, Catriona L Patterson, Jeffrey W Priest, Gillian Stresman, Timothy William, Tock H Chua, Kevin Tetteh, Patrick Lammie, Chris Drakeley, Kimberly M Fornace. Front Public Health. 2022 Oct 25;10:924316. doi: 10.3389/fpubh.2022.924316. eCollection 2022.
In June 2021, the World Health Organization (WHO), recognizing the need for new diagnostics to support the control and elimination of onchocerciasis, published the target product profiles (TPPs) of new tests that would support the two most immediate needs: (a) mapping onchocerciasis in areas of low prevalence and (b) deciding when to stop mass drug administration programs. In both instances, the test should ideally detect an antigen specific for live, adult O. volvulus female worms. The preferred format is a field-deployable rapid test. For mapping, the test needs to be ≥ 60% sensitive and ≥ 99.8% specific, while to support stopping decisions, the test must be ≥ 89% sensitive and ≥ 99.8% specific. The requirement for extremely high specificity is dictated by the need to detect with sufficient statistical confidence the low seroprevalence threshold set by WHO. Surveys designed to detect a 1-2% prevalence of a given biomarker, as is the case here, cannot tolerate more than 0.2% of false-positives. Otherwise, the background noise would drown out the signal. It is recognized that reaching and demonstrating such a stringent specificity criterion will be challenging, but test developers can expect to be assisted by national governments and implementing partners for adequately powered field validation.
Marco A. Biamonte ,Paul T. Cantey,Yaya I. Coulibaly,Katherine M. Gass,Louise C. Hamill,Christopher Hanna,Patrick J. Lammie,Joseph Kamgno,Thomas B. Nutman,David W. Oguttu,Dieudonné P. Sankara,Wilma A. Stolk,Thomas R. Unnasch. PLoS Negl Trop Dis. 2022 Aug 3;16(8):e0010682. doi: 10.1371/journal.pntd.0010682.
Background: Integrated surveillance for multiple diseases can be an efficient use of resources and advantageous for national public health programs. Detection of IgG antibodies typically indicates previous exposure to a pathogen but can potentially also serve to assess active infection status. Serological multiplex bead assays have recently been developed to simultaneously evaluate exposure to multiple antigenic targets. Haiti is an island nation in the Caribbean region with multiple endemic infectious diseases, many of which have a paucity of data for population-level prevalence or exposure.
Methods: A nationwide serosurvey occurred in Haiti from December 2014 to February 2015. Filter paper blood samples (n = 4,438) were collected from participants in 117 locations and assayed for IgG antibodies on a multiplex bead assay containing 15 different antigens from 11 pathogens: Plasmodium falciparum, Toxoplasma gondii, lymphatic filariasis roundworms, Strongyloides stercoralis, chikungunya virus, dengue virus, Chlamydia trachomatis, Treponema pallidum, enterotoxigenic Escherichia coli, Entamoeba histolytica, and Cryptosporidium parvum.
Results: Different proportions of the Haiti study population were IgG seropositive to the different targets, with antigens from T. gondii, C. parvum, dengue virus, chikungunya virus, and C. trachomatis showing the highest rates of seroprevalence. Antibody responses to T. pallidum and lymphatic filariasis were the lowest, with <5% of all samples IgG seropositive to antigens from these pathogens. Clear trends of increasing seropositivity and IgG levels with age were seen for all antigens except those from chikungunya virus and E. histolytica. Parametric models were able to estimate the rate of seroconversion and IgG acquisition per year for residents of Haiti.
Conclusions: Multiplex serological assays can provide a wealth of information about population exposure to different infectious diseases. This current Haitian study included IgG targets for arboviral, parasitic, and bacterial infectious diseases representing multiple different modes of host transmission. Some of these infectious diseases had a paucity or complete absence of published serological studies in Haiti. Clear trends of disease burden with respect to age and location in Haiti can be used by national programs and partners for follow-up studies, resource allocation, and intervention planning.
YuYen Chan, Diana Martin, Kimberly E Mace, Samuel E Jean, Gillian Stresman, Chris Drakeley, Michelle A Chang, Jean F Lemoine, Venkatachalam Udhayakumar, Patrick J Lammie, Jeffrey W Priest, Eric William Rogier. Front Public Health. 2022 Jun 9;10:897013. doi: 10.3389/fpubh.2022.897013. eCollection 2022.
A key component to achieving the global goal of elimination of lymphatic filariasis (LF) is the availability of appropriate tools for disease mapping, monitoring, and surveillance. However, the development of these tools for a neglected disease such as LF can be a challenge. The lack of a commercial market and low familiarity with these diseases leave little incentive for diagnostic manufacturers to invest in this space. The Filarial Test Strip (FTS) development story provides a case study on how a multi-stakeholder, public-private partnership model facilitated the development, evaluation, and introduction of a new monitoring and surveillance tool for LF. This paper will reflect on the experience with the FTS and document the process from development of the target product profile to adoption and scale-up in country programs. Lessons learned from both the successes and challenges experienced during this process may help inform future efforts to develop and introduce new diagnostic or surveillance tools for neglected diseases.
As lymphatic filariasis (LF) programs move closer to established targets for validation elimination of LF as a public health problem, diagnostic tools capable of supporting the needs of the programs are critical for success. Known limitations of existing diagnostic tools make it challenging to have confidence that program endpoints have been achieved. In 2019, the World Health Organization (WHO) established a Diagnostic Technical Advisory Group (DTAG) for Neglected Tropical Diseases tasked with prioritizing diagnostic needs including defining use-cases and target product profiles (TPPs) for needed tools. Subsequently, disease-specific DTAG subgroups, including one focused on LF, were established to develop TPPs and use-case analyses to be used by product developers. Here, we describe the development of two priority TPPs for LF diagnostics needed for making decisions for stopping mass drug administration (MDA) of a triple drug regimen and surveillance. Utilizing the WHO core TPP development process as the framework, the LF subgroup convened to discuss and determine attributes required for each use case. TPPs considered the following parameters: product use, design, performance, product configuration and cost, and access and equity. Version 1.0 TPPs for two use cases were published by WHO on 12 March 2021 within the WHO Global Observatory on Health Research and Development. A common TPP characteristic that emerged in both use cases was the need to identify new biomarkers that would allow for greater precision in program delivery. As LF diagnostic tests are rarely used for individual clinical diagnosis, it became apparent that reliance on population-based surveys for decision making requires consideration of test performance in the context of such surveys. In low prevalence settings, the number of false positive test results may lead to unnecessary continuation or resumption of MDA, thus wasting valuable resources and time. Therefore, highly specific diagnostic tools are paramount when used to measure low thresholds. The TPP process brought to the forefront the importance of linking use case, program platform and diagnostic performance characteristics when defining required criteria for diagnostic tools.
Kimberly Y Won, Katherine Gass, Marco Biamonte, Daniel Argaw Dagne, Camilla Ducker, Christopher Hanna, Achim Hoerauf, Patrick J Lammie, Sammy M Njenga, Rahmah Noordin, Kapa D Ramaiah, Reda Ramzy, Ronaldo G Carvalho Scholte, Anthony W Solomon, Ashley A Souza, Jordan Tappero, Emily Toubali, Gary J Weil, Steven A Williams, Jonathan D King. PLoS Negl Trop Dis 15(11): e0009968. https://doi.org/10.1371/journal.pntd.0009968
Lymphatic filariasis (LF) is a major public health problem globally and in the Pacific Region. The Global Programme to Eliminate LF has made great progress but LF is persistent and resurgent in some Pacific countries and territories. Samoa remains endemic for LF despite elimination efforts through multiple two-drug mass drug administrations (MDA) since 1965, including renewed elimination efforts started in 1999 under the Pacific Programme for Elimination of LF (PacELF). Despite eight rounds of national and two rounds of subnational MDA under PacELF, Samoa failed transmission assessment surveys (TAS) in all three evaluation units in 2017. In 2018, Samoa was the first to distribute countrywide triple-drug MDA using ivermectin, diethylcarbamazine (DEC), and albendazole. This paper provides a review of MDAs and historical survey results from 1998 to 2017 in Samoa and highlights lessons learnt from LF elimination efforts, including challenges and potential ways to overcome them to successfully achieve elimination.
Patricia M Graves, Hayley Joseph, Shaun P Coutts, Helen J Mayfield, Fuatai Maiava, Tile Ann Ah Leong-Lui, Palanitina Tupuimatagi Toelupe, Vailolo Toeaso Iosia, Siatua Loau, Paulo Pemita, Take Naseri, Robert Thomsen, Alvaro Berg Soto, Thomas R Burkot, Peter Wood, Wayne Melrose, Padmasiri Aratchige, Corinne Capuano, Sung Hye Kim, Masayo Ozaki, Aya Yajima, Patrick J Lammie, Eric Ottesen, Lepaitai Hansell, Rasul Baghirov, Colleen L Lau, Kazuyo Ichimori. Adv Parasitol. 2021;114:27-73. doi: 10.1016/bs.apar.2021.03.002
Mapping is a prerequisite for effective implementation of interventions against neglected tropical diseases (NTDs). Before the accelerated WHO/AFRO NTD Mapping Project was initiated in 2014, mapping efforts in many countries were frequently carried out in an ad hoc and nonstandardized fashion. In 2013, there were at least 2,200 different districts (of the 4,851 districts in the WHO African region) that still required mapping, and in many of these districts, more than one disease needed to be mapped. During its 3-year duration from January 2014 through the end of 2016, the project carried out mapping surveys for one or more NTDs in at least 2,500 districts in 37 African countries. At the end of 2016, most (90%) of the 4,851 districts had completed the WHO-required mapping surveys for the five targeted Preventive Chemotherapy (PC)-NTDs, and the impact of this accelerated WHO/AFRO NTD Mapping Project proved to be much greater than just the detailed mapping results themselves. Indeed, the AFRO Mapping Project dramatically energized and empowered national NTD programs, attracted donor support for expanding these programs, and developed both a robust NTD mapping database and data portal. By clarifying the prevalence and burden of NTDs, the project provided not only the metrics and technical framework for guiding and tracking program implementation and success but also the research opportunities for developing improved diagnostic and epidemiologic sampling tools for all 5 PC-NTDs-lymphatic filariasis, onchocerciasis, schistosomiasis, soil-transmitted helminthiasis, and trachoma.
Maria P Rebollo, Adiele Nkasiobi Onyeze, Alexandre Tiendrebeogo, Mutale Nsakashalo Senkwe, Benido Impouma, Kisito Ogoussan, Honorat G M Zouré, Kebede Deribe, Jorge Cano, Ekoue Boniface Kinvi, Andrew Majewski, Eric A Ottesen, Patrick Lammie. Am J Trop Med Hyg. 2021 Apr 26;tpmd201538. doi: 10.4269/ajtmh.20-1538
