Adherence to Hygiene Protocols and Doxycycline Therapy in Ameliorating Lymphatic Filariasis Morbidity in an Endemic Area Post-Interruption of Disease Transmission in Ghana.

Filarial lymphedema (LE) remains a significant global problem despite the progress made toward elimination of lymphatic filariasis (LF). In Ghana, the main approach to LF is preventive chemotherapy, but this has minimal impact on individuals who have already developed LE. In 2018-2020, a 24-month randomized, double-blind, placebo-controlled trial was conducted to evaluate the efficacy of stringent hygiene measures using the Essential Package of Care with or without additional administration of doxycycline (DOX) to improve filarial leg LE. This study enrolled 356 participants with LE stages 1-3 from two districts in the Upper East Region of Ghana. In addition to regular training on appropriate care for their affected legs, participants were randomized to receive 6 weeks of either 200 mg/day DOX (n = 117), 100 mg/day DOX (n = 120), or matching placebo (n = 119). Participants were seen every 2 months, with clinical measurements done at 6, 12, 18, and 24 months to assess the status of affected legs. There was a trend toward later appearance of acute attacks after DOX, but surprisingly, DOX showed no effect on LE stage progression. In all groups, leg LE improvement was more common (DOX 200 mg: n = 23 [20%]; DOX 100 mg: n = 23 [19.5%]; placebo: n = 32 [27.4%]) than LE worsening (DOX 200 mg: n = 2 [1.7%]; DOX 100 mg: n = 3 [2.5%]; placebo: n = 2 [1.7%]). Overall, these data show a strong benefit from adherence to a strict hygiene protocol, with some added potential benefit for DOX in preventing acute attacks.

Designing of a chimeric multiepitope vaccine against bancroftian lymphatic filariasis through immunoinformatics approaches.

The filarial worms of Wuchereria bancrofti are the primary cause of lymphatic filariasis (LF), a mosquito-borne disease among the neglected tropical parasitic diseases. Considering the global endemic consequences of the disease, there is a need to develop a successful vaccine candidate against LF. Using advanced immunoinformatics approaches, we designed two multiepitope vaccines targeting W. bancrofti's glutathione S-transferase and thioredoxin. Therefore, we predicted several MHC-1, MHC-2, and B-cell epitopes from these proteins and mapped two vaccine candidates (V1 and V2). The vaccines were subsequently employed for physicochemical analysis, structural prediction and validation, docking and normal mode analysis, codon optimization, and immune simulation. The selected MHC-1, MHC-2, and B-cell epitopes were antigenic without allergenicity or toxicity. The designed vaccines were expected to be soluble, stable proteins under physiological conditions. Compared to V2, V1's secondary and tertiary structures were simultaneously favorable, with Ramachandran plot analysis revealing 95.6% residues in favored areas. Subsequently, the molecular docking analysis indicated that the V1 had a high binding affinity for the TLR-2, TLR-4 and TLR-5, as suggested by the docking scores of -1248.7, -1038.5 and -1562.8, respectively. The NMA of these complexes further indicated their structural flexibility. Molecular dynamics simulations of V1-TLR complexes revealed V1-TLR-4 as the most stable, with the lowest free energy and minimal fluctuations, indicating the strongest binding affinity. The results of the codon optimization showed high levels of expression, with a favorable CAI score (<1.0). A three-dose vaccination analysis showed significant and persistent immunological responses, including adaptive and innate immune responses. The findings emphasize the potential of the V1 against W. bancrofti, but further validation is required through in vitro, in vivo, and clinical trials.

The long and winding road towards new treatments against lymphatic filariasis and onchocerciasis.

Although lymphatic filariasis and onchocerciasis have been targeted for global elimination, these helminth infections are still a major public health problem across the tropics and subtropics. Despite decades of research, treatment options remain limited and drugs that completely clear the infections, and can be used on a large scale, are still unavailable. In the present review we discuss the strengths and weaknesses of currently available treatments and new ones in development. Novel candidates (corallopyronin A, DNDi-6166, emodepside, and oxfendazole) are currently moving through (pre)clinical development, while the development of two candidates (AWZ1066S and ABBV-4083/flubentylosin) was recently halted. The preclinical R&D pipeline for filarial infections continues to be limited, and recent setbacks highlight the importance of continuous drug discovery and testing.

The impact of the National Programme to Eliminate Lymphatic Filariasis on filariasis morbidity in Sri Lanka: Comparison of current status with retrospective data following the elimination of lymphatic filariasis as a public health problem.

INTRODUCTION: Sri Lanka implemented the National Programme for Elimination of Lymphatic Filariasis (NPELF) in its endemic regions in 2002. Five annual rounds of mass drug administration using the two-drug combination diethylcarbamazine (DEC) and albendazole led to sustained reductions in infection rates below threshold levels. In 2016, WHO validated that Sri Lanka eliminated lymphatic filariasis as a public health problem. OBJECTIVE: To explore the impact of the NPELF on lymphatic filariasis morbidity in Sri Lanka. METHODS: Passive Case Detection (PCD) data maintained in filaria clinic registries from 2006-2022 for lymphoedema and hospital admission data for managing hydroceles/spermatoceles from 2007-2022 were analyzed. The morbidity status in 2022 and trends in overall and district-wise PCD rates were assessed. Poisson log-linear models were used to assess the trends in PCD for endemic regions, including district-wise trends and hospital admissions for the management of hydroceles/spermatoceles. RESULTS: In 2022, there were 566 new lymphoedema case visits. The mean (SD) age was 53.9 (16.0) years. The staging was done for 94% of cases, of which 79% were in the early stages (57.3% and 21.4% in stages two and one, respectively). Western Province had the highest caseload (52%), followed by the Southern (32%) and Northwestern (16%) Provinces, respectively. The reported lymphoedema PCD rate in 2022 was 0.61 per 10,000 endemic population. The overall PCD rate showed a decline of 7.6% (95%CI: 4.9% - 10.3%) per year (P < 0.0001) from 2007 to 2022. A steady decline was observed in Colombo, Gampaha and Kurunegala districts, while Kalutara remained static and other districts showed a decline in recent years. Further, admissions for inpatient management of hydroceles/spermatoceles showed a declining trend after 2015. CONCLUSIONS: The PCD rates of lymphoedema and hydroceles/spermatoceles showed a declining trend in Sri Lanka after the implementation of the NPELF.

Operational research to inform post-validation surveillance of lymphatic filariasis in Tonga study protocol: History of lymphatic filariasis elimination, rational, objectives, and design.

BACKGROUND: Lymphatic filariasis (LF), a mosquito-borne helminth infection, is an important cause of chronic disability globally. The World Health Organization has validated eight Pacific Island countries as having eliminated lymphatic filariasis (LF) as a public health problem, but there are limited data to support an evidence-based approach to post-validation surveillance (PVS). Tonga was validated as having eliminated LF in 2017 but no surveillance has been conducted since 2015. This paper describes a protocol for an operational research project investigating different PVS methods in Tonga to provide an evidence base for national and regional PVS strategies. METHODS: Programmatic baseline surveys and Transmission Assessment Surveys conducted between 2000-2015 were reviewed to identify historically 'high-risk' and 'low-risk' schools and communities. 'High-risk' were those with LF antigen (Ag)-positive individuals recorded in more than one survey, whilst 'low-risk' were those with no recorded Ag-positives. The outcome measure for ongoing LF transmission will be Ag-positivity, diagnosed using Alere™ Filariasis Test Strips. A targeted study will be conducted in May-July 2024 including: (i) high and low-risk schools and communities, (ii) boarding schools, and (iii) patients attending a chronic-disease clinic. We estimate a total sample size of 2,010 participants. CONCLUSIONS: Our methodology for targeted surveillance of suspected 'high-risk' populations using historical survey data can be adopted by countries when designing their PVS strategies. The results of this study will allow us to understand the current status of LF in Tonga and will be used to develop the next phase of activities.

LEDoxy-SL: A Placebo-Controlled, Double-Blind, Randomized, 24-Month Trial of Six Weeks of Daily Doxycycline Plus Hygiene-Based Essential Care for Reducing Progression of Filarial Lymphedema in Sri Lanka.

Morbidity management of filarial lymphedema remains a challenge even during the post-lymphatic filariasis elimination era in Sri Lanka despite provision of the predominantly hygiene-based WHO Essential Package of Care. Because prior studies have suggested that 6 weeks of doxycycline may reduce progression of limb lymphedema, we conducted a randomized, placebo-controlled, superiority study to evaluate this possibility in Sri Lanka. Patients aged 14 to 65 years with lymphedema in one or both legs received either 200 mg of doxycycline daily for 6 weeks or matching placebo. The primary efficacy endpoint was improvement or lack of progression in lymphedema stage at 24 months postenrollment. Secondary endpoints included change in lymphedema stage at 12 and 24 months, frequency of acute adenolymphangitis episodes, and perceived disability measured by the WHO Disability Assessment Schedule 2.0 (WHODAS 2.0). Training and supplies for limb hygiene were provided throughout the study. Two hundred participants (100 in each arm) with lymphedema of Dreyer stages 1 to 3 were enrolled. By the end of the 2-year study, 29% of the doxycycline patients and 34% of those on placebo showed improvement (i.e., a decrease in lymphedema stage), whereas 11% and 15% of the two groups showed worsening of the lymphedema. Adenolymphangitis rates were comparable in the two groups (43 doxycycline and 38 placebo recipients), although attacks lasted slightly longer in placebo patients (6.5 days versus 5.2 days). In both groups, perceived disability improved initially, with partial rebound in the second year. Only 34 adverse events affecting 24 patients (11%) occurred during the 6-week treatment period. Although doxycycline did not significantly impact lymphedema progression in this study, the results clearly indicate that clinical and personal benefits can be obtained from intensive hygiene management alone.

Acceptance of Mass Drug Administration for Prophylaxis against Lymphatic Filariasis in a Tribal Endemic Area: A Descriptive Cross-sectional Study.

BACKGROUND: India is at a critical stage to eliminate filariasis. Uncovering the factors governing may help taking appropriate measures to achieve the goal. OBJECTIVES: This study evaluated the acceptance of "mass drug administration" (MDA) for prophylaxis against filariasis and the factors facilitating and interfering with it. MATERIALS AND METHODS: A cross-sectional study was conducted in a tribal endemic area of India from May 2022 to October 2022. A validated 29-item self-administered questionnaire was used to collect the data. Items were grouped under "knowledge," "social processes," "think and feel," "practical factors," and "motivation/hesitancy" domains. RESULTS: Of 101 participants, majority were aware of the disease (92.1%), its vector (74.3%), at least one disability caused (87.2%), and governmental scheme of MDA (69.3%). Two-thirds never received and 85.1% did not receive MDA within 1 year. 68.3% refused of distribution of MDA to their doorstep. Majority were concerned for getting MDA for self and their family/friends; however, 49.5% showed inability to take independent decision. More than 30% disagreed to get MDA had it been available. The region with the highest concerns for adverse drug effects showed minimum MDA consumption than others (P < 0.05). MDA acceptance/consumption was significantly associated with knowledge about disability caused, distribution of drugs by a health-care representative to doorstep, behavior of the representative, and concerns about potential adverse drug effects. CONCLUSION: MDA coverage was inadequate in the study population. Level of knowledge, practical difficulties in getting drugs, inapt thinking/concerns, motivation, awareness about disabilities caused, door-to-door drug distribution, and behavior of health-care representative(s), were identified as factors significantly affecting acceptance of MDA.

Triple-drug therapy with ivermectin, diethylcarbamazine and albendazole for the acceleration of lymphatic filariasis elimination in Kenya: Programmatic implementation and results of the first impact assessment.

The World Health Organization (WHO) endorsed the use of triple-drug mass drug administration (MDA) regimen with ivermectin, diethylcarbamazine (DEC) and albendazole (commonly abbreviated as IDA) to accelerate the elimination of lymphatic filariasis (LF) as a public health problem in settings where onchocerciasis is not co-endemic. The National Programme for Elimination of LF (NPELF) in Kenya was among the first adopters of the IDA-MDA and two annual rounds were provided in 2018 and 2019 to the residents of Lamu County and Jomvu sub-County in the coast region. This study documented the feasibility of successfully delivering the two rounds of IDA-MDA. An operational research study was undertaken to determine efficient sampling strategies, indicators, and the appropriate population groups that could be used for the monitoring and evaluation of LF programs using IDA-MDA for the elimination of the disease as a public health problem. Two cross-sectional surveys were conducted at baseline in 2018 before IDA-MDA and an impact assessment 17 months after the second round of IDA-MDA. The reported epidemiological treatment coverage was at least 80% in all implementation units during each round of IDA-MDA. Blood samples were tested for filarial antigenemia using commercial Filariasis Test Strips (FTS) and any individual found to be positive was tested again at night for the presence of microfilariae in finger prick blood smears using microscopy. The overall prevalence of circulating filarial antigen (CFA) was relatively low at the baseline survey with Jomvu having 1.39% (95% CI: 0.91, 2.11) and Lamu having 0.48% (95% CI: 0.21, 1.13). Significant reduction in CFA prevalence was observed during the impact assessment after the two annual rounds of mass treatment. The overall relative reduction (%) in CFA prevalence following the two rounds of MDA with IDA was significant in both Jomvu (52.45%, Z = -2.46, P < 0.02) and Lamu (52.71%, Z = -1.97, P < 0.05). Heterogeneity, however, was observed in the CFA prevalence reduction between random and purposive clusters, as well as between adult and child populations. The results of the impact assessment survey offered strong evidence that it was safe to stop the IDA-MDA in the two EUs because transmission appears to have been interrupted. It is also important to implement a post-treatment surveillance system which would enable efficient detection of any recrudescence of LF transmission at a sub-evaluation unit level. Our findings show that IDA-MDA may be considered for acceleration of LF elimination in other settings where onchocerciasis is not co-endemic.

Evaluation of the International Task Force for Disease Eradication: A Review of Past Deliberations.

The International Task Force for Disease Eradication (ITFDE) was formed at The Carter Center in 1988. Its primary purpose is to review activities and provide recommendations related to programs focused on eradication. The ITFDE also considers opportunities for disease elimination and improved control. Over the last two decades, the ITFDE has held 33 meetings, discussed 22 diseases, and made 244 recommendations. This report aims to analyze the patterns in recommendations made by the ITFDE between 2001 and 2022 and assess the ITFDE's role, impacts, and successes in advancing elimination and eradication efforts for selected diseases. Using a thematic analysis, recommendation categories were crafted, followed by a scoping review to determine evidence of implementation for each recommendation. Categories of recommendations included research (24%), leadership (20%), medical (17%), advocacy (11%), collaboration (13%), development (8%), and financial (8%). We determined that 123 (50.4%) ITFDE recommendations were implemented in some form. Notably, the ITFDE has helped raise the profile of neglected tropical diseases. Four salient outcomes include 1) the identification of the potential eradicability of lymphatic filariasis (1993), 2) the recognition of the critical need for improved treatments of human African trypanosomiasis (2002), 3) a recommendation for the elimination of lymphatic filariasis and malaria from Hispaniola (2006), and 4) recommendations for effective and safe ways to avoid disruption of elimination and eradication programs during the COVID-19 pandemic (2020). This review of the ITFDE will help to devise new approaches to monitor its impact in the future.

Efficacy of ivermectin and albendazole combination in suppressing transmission of lymphatic filariasis following mass administration in Tanzania: a prospective cohort study.

BACKGROUND: Preventive chemotherapy with ivermectin and albendazole (IA) in mass drug administration (MDA) programs for all at-risk populations is the core public health intervention to eliminate lymphatic filariasis (LF). Achieving this goal depends on drug effectiveness in reducing parasite reservoirs in the community to halt transmission. We assessed the efficacy of ivermectin and albendazole in clearing microfilariae and circulating filarial antigens (CFA) following MDA. METHODS: This community-based prospective study was conducted in Mkinga district, Tanga region, Tanzania, from November 2018 to June 2019. A total of 4115 MDA-eligible individuals were screened for CFA using Filarial test strips. CFA positives were re-examined for microfilariae by microscopy. CFA and microfilariae positive individuals were enrolled and received IA through MDA campaign. The status of microfilariae and CFA was monitored before MDA, and on day 7 and six-month following MDA. The primary efficacy outcomes were the clearance rates of microfilariae on day 7 and six-months, and CFA at 6 months of post-MDA. The McNemar test assessed the proportions of microfilariae positive pre- and post-MDA, while Chi-square tests were utilized to examine factors associated with CFA status six months post-MDA. RESULTS: Out of 4115 individuals screened, 239 (5.8%) tested positive for CFA, of whom 11 (4.6%) were also positive for microfilariae. Out of the ten microfilariae-positive individuals available for follow-up on day 7, nine tested negative, yielding a microfilariae clearance rate of 90% [95% confidence interval (CI): 59.6-98.2%]. Participants who tested negative for microfilariae on day 7 remained free of microfilariae six months after MDA. However, those who did not clear microfilariae on day-7 remained positive six-months post-MDA. The McNemar test revealed a significant improvement in microfilariae clearance on day 7 following MDA (P = 0.02). Out of 183 CFA-positive individuals who were available at 6-month follow-up, 160 (87.4%) remained CFA positive, while 23 became CFA negative. The CFA clearance rate at 6 months post-MDA was 12.6% (95% CI: 8.5-8.5%). There was no significant association of variability in ivermectin plasma exposure, measured by maximum concentration or area under the curve, and the clearance status of microfilariae or CFA post-MDA. CONCLUSIONS: Preventive chemotherapy with IA effectively clears microfilariae within a week. However, it is less effective in clearing CFA at six months of post-MDA. The low clearance rate for filarial antigenemia underscores the need for alternative drug combinations and additional preventive measures to achieve LF elimination by 2030.

Ongoing transmission of lymphatic filariasis in Samoa 4.5 years after one round of triple-drug mass drug administration.

BACKGROUND: Lymphatic filariasis (LF) remains a significant global issue. To eliminate LF as a public health problem, the World Health Organization (WHO) recommends multiple rounds of mass drug administration (MDA). In certain scenarios, including when elimination targets have not been met with two-drug MDA, triple-drug MDA (using ivermectin, diethylcarbamazine and albendazole) is recommended. In this study, we report on antigen (Ag) and microfilaria (Mf) prevalence in eight primary sampling units (PSUs) in Samoa 4.5 years after one round of triple-drug MDA. METHODOLOGY: In 2023, community surveys were conducted in eight PSUs that had been surveyed previously in 2018 (between 1.5 and 3.5 months post triple-drug MDA) and 2019 (six to eight-months post triple-drug MDA). Fifteen houses were randomly selected in each PSU with household members aged ≥ 5 years invited to participate. Blood samples were tested for Ag and Mf. PRINCIPAL FINDINGS: Ag-positive participants were observed in six of the eight PSUs, and Ag prevalence was significantly above the 1% threshold in four PSUs. The presence of Mf-positive participants in five PSUs confirms the presence of residual active infections. CONCLUSIONS/SIGNIFICANCE: This study provides evidence of persistent LF transmission in Samoa 4.5 years after one round of triple-drug MDA, confirming that one round was insufficient for interruption of transmission in this setting. Our findings highlight the negative impact of delaying MDA rounds, for example, due to public health emergencies.

Results of Integrated Transmission Assessment Surveys for Lymphatic Filariasis and Malaria in Haiti, 2017-2022.

Haiti is endemic for lymphatic filariasis (LF) and malaria, two mosquito-transmitted parasitic diseases targeted for elimination. The World Health Organization recommends a transmission assessment survey (TAS-1) to determine if LF prevalence is significantly beneath putative transmission thresholds (<2% antigen prevalence in Haiti, where Culex is the primary vector for Wuchereria bancrofti) to stop mass drug administration (MDA). Repeated TASs (TAS-2 and TAS-3) are recommended at 2-3-year intervals during post-treatment surveillance. From 2017 to 2022, The Carter Center assisted the Haitian Ministry of Public Health and Population in conducting 15 TASs in 11 evaluation units (EUs) encompassing 54 of the country's 146 districts. Children 6-7 years old were assessed for circulating filarial antigen (CFA) by Filariasis Test Strip: n = 5,239 in TAS-1; n = 11,866 in TAS-2; and n = 1,842 in TAS-3, of whom eight (0.15%), 20 (0.17%), and eight (0.43%) tested positive, respectively. The number of positive results in children was less than the threshold in each EU. When available, participants (n = 16,663) were also tested for malaria by rapid diagnostic test, with 31 (0.19%) children testing positive for Plasmodium falciparum. Integrated TASs provided an efficient means to collect epidemiological data for LF and malaria in Haiti. Results indicated thresholds for stopping and maintaining the halt of MDA for LF have been achieved in all EUs, with the halt of MDA for 571,358 people in four districts and the first TAS-3 surveys conducted in Haiti. Investigations are needed to assess the potential of ongoing LF transmission, especially in areas where CFA-positive samples were detected in TAS-3.

Modelling the cost of engage & treat and test & treat strategies towards the elimination of lymphatic filariasis in Ghana.

BACKGROUND: Despite several years of LF-MDA implementation, Ghana still has some districts with mf prevalence >1%, partly due to poor treatment coverage levels resulting from non-participation in MDA. To address the challenges, we implemented Engage & Treat (E&T) and Test & Treat (T&T) strategies for individuals who miss or refuse MDA respectively, in a hotspot district, enabling us to reach many of those who seldom, or never, take part in MDA. This financial cost study was undertaken to analyse data on the LF-MDA, E&T and T&T implementation in 2021 and the financial cost to inform the rollout of the E&T and T&T as mop-up strategies in future LF-MDAs. METHODS: This costing study analysed cost data from the 2021 LF-MDA implementation activities carried out by the Neglected Tropical Diseases (NTD) programme of the Ghana Health Service and the SENTINEL study, carried out in Ahanta West district for the two interventions (i.e., E&T and T&T). The 2021 Ghana Population and Housing Census data was used to estimate the LF-MDA-eligible population. The financial cost per person treated was estimated and these costs were applied to the projected population to obtain the financial cost for subsequent years. RESULTS: Implementing MDA mop-up strategies either through the E&T or T&T to improve coverage comes at an additional cost to the elimination goals. For example, in 2024 the projected cost per person treated by the routine LF-MDA is estimated at US$0.83. The cost using the integrated LF-MDA and the E&T, T&T led by the NTD programme or T&T integrated into the health system was estimated at US$1.62, US$2.88, and US$2.33, respectively, for the same year. Despite the increased cost, the proposed combined LF-MDA and mop-up strategies will have a higher estimated population treated for 2024 (i.e., 1,392,211) compared to the routine LF-MDA approach (i.e., 988,470) for the same year. CONCLUSION: Combining LF-MDA with E&T/T&T mop-up strategies, despite their high costs, may provide NTD Programmes with the options of improving treatment coverage and reaching the LF elimination target sooner, given that the routine LF-MDA alone approach has been implemented for many years with some districts yet to reach the elimination targets.

An Ensemble Framework for Projecting the Impact of Lymphatic Filariasis Interventions Across Sub-Saharan Africa at a Fine Spatial Scale.

BACKGROUND: Lymphatic filariasis (LF) is a neglected tropical disease targeted for elimination as a public health problem by 2030. Although mass treatments have led to huge reductions in LF prevalence, some countries or regions may find it difficult to achieve elimination by 2030 owing to various factors, including local differences in transmission. Subnational projections of intervention impact are a useful tool in understanding these dynamics, but correctly characterizing their uncertainty is challenging. METHODS: We developed a computationally feasible framework for providing subnational projections for LF across 44 sub-Saharan African countries using ensemble models, guided by historical control data, to allow assessment of the role of subnational heterogeneities in global goal achievement. Projected scenarios include ongoing annual treatment from 2018 to 2030, enhanced coverage, and biannual treatment. RESULTS: Our projections suggest that progress is likely to continue well. However, highly endemic locations currently deploying strategies with the lower World Health Organization recommended coverage (65%) and frequency (annual) are expected to have slow decreases in prevalence. Increasing intervention frequency or coverage can accelerate progress by up to 5 or 6 years, respectively. CONCLUSIONS: While projections based on baseline data have limitations, our methodological advancements provide assessments of potential bottlenecks for the global goals for LF arising from subnational heterogeneities. In particular, areas with high baseline prevalence may face challenges in achieving the 2030 goals, extending the "tail" of interventions. Enhancing intervention frequency and/or coverage will accelerate progress. Our approach facilitates preimplementation assessments of the impact of local interventions and is applicable to other regions and neglected tropical diseases.

Impact of conflict on the elimination targets of lymphatic filariasis, schistosomiasis and soil-transmitted helminths in Cabo Delgado province, Mozambique.

BACKGROUND: Mozambique has one of the highest burdens of neglected tropical diseases in Africa. Lymphatic filariasis, schistosomiasis and soil-transmitted helminths are being targeted for elimination as part of integrated mass drug administration campaigns. The progress made towards interruption of transmission has been affected by recent conflict in Cabo Delgado province. The aim of this paper was to determine the potential impact of this crisis on the neglected tropical diseases programme and the challenges in reaching the elimination goals of 2030. METHODOLOGY: A desk-based secondary data analysis was conducted on publicly available sources of neglected tropical diseases, conflict incidents, internally displaced persons and geographical access between 2020 and 2022. Data were summarised and mapped using GIS software. A combined risk stratified assessment at district level was developed with five classifications i) Very high-risk; ii) High-risk; iii) Medium to high-risk; iv) Medium risk; and v) Not at risk due to conflict absence but co-endemic. RESULTS: Lymphatic filariasis, schistosomiasis and soil-transmitted helminths were co-endemic in 115 out of 156 (74%) districts. Between 2020 and 2022 a total of 1,653 conflict-related incidents were reported, most of them in Cabo Delgado province (n = 1,397, 85%). A five-fold increase of internally displaced persons was recorded from April 2020 (n = 172,186) to November 2022 (n = 935,130). Geographical accessibility also deteriorated across the province with an increase from five (29%) in 2021 to seven (41%) districts in 2022 classified as hard-to-reach. The combined risk stratification identified that most districts in Cabo Delgado province had medium to high-risk (n = 7; 41%); very high-risk (n = 5, 29%); medium risk (n = 3, 18%); high-risk (n = 2, 12%). CONCLUSION: Most of the districts of Cabo Delgado were considered to be at risk of not meeting the neglected tropical diseases road map 2030 targets due to the humanitarian crisis ongoing. There is the need for practical strategies and funding to overcome these hostile challenges.

Entomological assessment in 'hotspots' of four lymphatic filariasis endemic districts, Central Nepal during post-MDA surveillance.

BACKGROUND OBJECTIVES: Annual mass drug administration (MDA) is the main strategy to interrupt the transmission of lymphatic filariasis (LF) in the community. The main aim of monitoring the MDA program, for its effectiveness and interruption of LF is the post-MDA surveillance using antigen survey in children born after MDA. The latest technique of new research suggests that xenomonitoring is an effective tool for monitoring LF intervention. The objective of this study was to assess the W. bancrofti infection/or infectivity in vector mosquitoes by xenomonitoring during post-MDA surveillance. METHODS: A descriptive cross-sectional study was conducted in the hotspots of selected four districts of Central Nepal. A gravid trap technique was used for sampling mosquitoes. Infection/or infectivity was determined via the dissection of vector mosquitoes. Anopheles, Aedes, Armigerus and Culex species were collected from hotspots of four endemic districts, two from the hilly region (Lalitpur and Dhading) and two from Terai region (Bara and Mahottari) of Central Nepal. RESULTS: A total of 4450 mosquitoes belonging to four genera, Anopheles, Culex, Armigeres, and Aedes were collected from four hotspots. The distribution of Culex quinquefasciatus was found to be the highest, 88.9% (n=3955/4450) followed by Cx. vishnui (4.5%), Armigeres sp (5.8%), An. culicifascies (0.2%), Aedes spp (0.8%). The proportion of female mosquitoes trapped is significantly higher. A total of 3344 parous Cx. quinquefasciatus mosquitoes were dissected for any larval stage of W. bancrofti. We could not find any filarial infection in dissected mosquito samples. INTERPRETATION CONCLUSION: We conclude that the gravid trap is an efficient tool for the collection of gravid Cx. quinquefasciatus mosquitoes for xenomonitoring studies of filariasis endemic regions. Vector composition indicated a maximum number of vector mosquitoes of lymphatic filariasis were trapped compared with the other three species. Distribution and density of Cx. quinquefasciatus was found highest in four hotspots of endemic districts. None of the Cx. quinquefasciatus dissected were found to be infected by larval forms of filaria. Since the low levels of infection persistence in the human population in these hot spots, vector infection and infectivity can't be ignored. Microscopic xenomonitoring at a low level of infection persistent is less likely to be efficient so molecular xenomonitoring along with a large sample should be required in each of the hot spots of the districts. Additionally, area is receptive so further vector control intervention should be required to reduce the risk of resurgence of infection.

Immune targeting of filarial glutaredoxin through a multi-epitope peptide-based vaccine: A reverse vaccinology approach.

Despite the efforts of global programme to eliminate lymphatic filariasis (GPELF), the threat of lymphatic filariasis (LF) still looms over humanity in terms of long-term disabilities, and morbidities across the globe. In light of this situation, investigators have chosen to focus on the development of immunotherapeutics targeting the physiologically important filarial-specific proteins. Glutaredoxin (16.43 kDa) plays a pivotal role in filarial redox biology, serving as a vital contributor. In the context of the intra-host survival of filarial parasites, this antioxidant helps in mitigating the oxidative stress imposed by the host immune system. Given its significant contribution, the development of a vaccine targeting glutaredoxin holds promise as a new avenue for achieving a filaria-free world. Herein, multi-epitope-based vaccine was designed using advanced immunoinformatics approach. Initially, 4B-cell epitopes and 6 T-cell epitopes (4 MHC I and 2 MHC II) were identified from the 146 amino acid long sequence of glutaredoxin of the human filarid, Wuchereria bancrofti. Subsequent clustering of these epitopes with linker peptides finalized the vaccine structure. To boost TLR-mediated innate immunity, TLR-specific adjuvants were incorporated into the designed vaccine. After that, experimental analyses confirm the designed vaccine, Vac4 as anefficient ligand of human TLR5 to elicit protective innate immunity against filarial glutaredoxin. Immune simulation further demonstrated abundant levels of IgG and IgM as crucial contributors in triggering vaccine-induced adaptive responses in the recipients. Hence, to facilitate the validation of immunogenicity of the designed vaccine, Vac4 was cloned in silico in pET28a(+) expression vector for recombinant production. Taken together, our findings suggest that vaccine-mediated targeting of filarial glutaredoxin could be a future option for intervening LF on a global scale.

Bioactive components in Psidium guajava extracts elicit biotoxic attributes and distinct antioxidant enzyme modulation in the larvae of vectors of lymphatic filariasis and dengue.

Control of mosquito vectors, which have caused a global disease burden, has employed various methods. However, the challenges posed by current physical and chemical methods have raised concerns about vector control programs, leading to the search for alternative methods that are less toxic, eco-friendly, and cost-effective. This study investigated the larvicidal potential of aqueous, methanol, and ethylacetate extracts of Guava (Psidium guajava) against Aedes aegypti and Culex quinquefasciatus larvae. Functional group and phytochemical characterization were performed using Fourier-Transform Infrared Spectroscopy (FTIR) and GC-MS analysis to identify the bioactive compounds in the extracts. Larval bioassays were conducted using WHO standard procedures at concentrations of 12.5, 25, 50, 125, and 250 mg/L, and mortality was recorded after 24, 48, and 72 h. Additionally, antioxidant enzyme profiles in the larvae were studied. All of the solvent extracts showed larvicidal activity, with the methanol extract exhibiting the highest mortality against Ae. aegypti and Cx. quinquefasciatus larvae, followed by aqueous and ethylacetate extracts. FTIR spectroscopic analysis revealed the presence of OH, C-H of methyl and methylene, CO and CC. The GC-MS analysis indicated that the methanol, aqueous, and ethylacetate extracts all had 27, 34, and 43 phytoactive compounds that were effective at causing larvicidal effects, respectively. Different concentrations of each extract significantly modulated the levels of superoxide dismutase, catalase, glutathione peroxidase, and reduced glutathione in larvae. This study's findings indicate the potential for developing environmentally friendly vector control products using the bioactive components of extracts from P. guajava leaves.

Predictive Value of Microfilariae-Based Stop-MDA Thresholds After Triple Drug Therapy With IDA Against Lymphatic Filariasis in Treatment-Naive Indian Settings.

Mass drug administration (MDA) of antifilarial drugs is the main strategy for the elimination of lymphatic filariasis (LF). Recent clinical trials indicated that the triple-drug therapy with ivermectin, diethylcarbamazine, and albendazole (IDA) is much more effective against LF than the widely used two-drug combinations (albendazole plus either ivermectin or diethylcarbamazine). For IDA-based MDA, the stop-MDA decision is made based on microfilariae (mf) prevalence in adults. In this study, we assess how the probability of eventually reaching elimination of transmission depends on the critical threshold used in transmission assessment surveys (TAS-es) to define whether transmission was successfully suppressed and triple-drug MDA can be stopped. This analysis focuses on treatment-naive Indian settings. We do this for a range of epidemiological and programmatic contexts, using the established LYMFASIM model for transmission and control of LF. Based on our simulations, a single TAS, one year after the last MDA round, provides limited predictive value of having achieved suppressed transmission, while a higher MDA coverage increases elimination probability, thus leading to a higher predictive value. Every additional TAS, conditional on previous TAS-es being passed with the same threshold, further improves the predictive value for low values of stop-MDA thresholds. An mf prevalence threshold of 0.5% corresponding to TAS-3 results in ≥95% predictive value even when the MDA coverage is relatively low.

Subnational Projections of Lymphatic Filariasis Elimination Targets in Ethiopia to Support National Level Policy.

BACKGROUND: Lymphatic filariasis (LF) is a debilitating, poverty-promoting, neglected tropical disease (NTD) targeted for worldwide elimination as a public health problem (EPHP) by 2030. Evaluating progress towards this target for national programmes is challenging, due to differences in disease transmission and interventions at the subnational level. Mathematical models can help address these challenges by capturing spatial heterogeneities and evaluating progress towards LF elimination and how different interventions could be leveraged to achieve elimination by 2030. METHODS: Here we used a novel approach to combine historical geo-spatial disease prevalence maps of LF in Ethiopia with 3 contemporary disease transmission models to project trends in infection under different intervention scenarios at subnational level. RESULTS: Our findings show that local context, particularly the coverage of interventions, is an important determinant for the success of control and elimination programmes. Furthermore, although current strategies seem sufficient to achieve LF elimination by 2030, some areas may benefit from the implementation of alternative strategies, such as using enhanced coverage or increased frequency, to accelerate progress towards the 2030 targets. CONCLUSIONS: The combination of geospatial disease prevalence maps of LF with transmission models and intervention histories enables the projection of trends in infection at the subnational level under different control scenarios in Ethiopia. This approach, which adapts transmission models to local settings, may be useful to inform the design of optimal interventions at the subnational level in other LF endemic regions.