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.

Unveiling the intricacies of allosteric regulation in aspartate kinase from the Wolbachia endosymbiont of Brugia Malayi: Mechanistic and therapeutic insights.

Aspartate kinase (AK), an enzyme from the Wolbachia endosymbiont of Brugia malayi (WBm), plays a pivotal role in the bacterial cell wall and amino acid biosynthesis, rendering it an attractive candidate for therapeutic intervention. Allosteric inhibition of aspartate kinase is a prevalent mode of regulation across microorganisms and plants, often modulated by end products such as lysine, threonine, methionine, or meso-diaminopimelate. The intricate and diverse nature of microbial allosteric regulation underscores the need for rigorous investigation. This study employs a combined experimental and computational approach to decipher the allosteric regulation of WBmAK. Molecular Dynamics (MD) simulations elucidate that ATP (cofactor) and ASP (substrate) binding induce a closed conformation, promoting enzymatic activity. In contrast, the binding of lysine (allosteric inhibitor) leads to enzyme inactivation and an open conformation. The enzymatic assay demonstrates the optimal activity of WBmAK at 28 °C and a pH of 8.0. Notably, the allosteric inhibition study highlights lysine as a more potent inhibitor compared to threonine. Importantly, this investigation sheds light on the allosteric mechanism governing WBmAK and imparts novel insights into structure-based drug discovery, paving the way for the development of effective inhibitors against filarial pathogens.

Reducing the Antigen Prevalence Target Threshold for Stopping and Restarting Mass Drug Administration for Lymphatic Filariasis Elimination: A Model-Based Cost-effectiveness Simulation in Tanzania, India and Haiti.

BACKGROUND: The Global Programme to Eliminate Lymphatic Filariasis (GPELF) aims to reduce and maintain infection levels through mass drug administration (MDA), but there is evidence of ongoing transmission after MDA in areas where Culex mosquitoes are the main transmission vector, suggesting that a more stringent criterion is required for MDA decision making in these settings. METHODS: We use a transmission model to investigate how a lower prevalence threshold (<1% antigenemia [Ag] prevalence compared with <2% Ag prevalence) for MDA decision making would affect the probability of local elimination, health outcomes, the number of MDA rounds, including restarts, and program costs associated with MDA and surveys across different scenarios. To determine the cost-effectiveness of switching to a lower threshold, we simulated 65% and 80% MDA coverage of the total population for different willingness to pay per disability-adjusted life-year averted for India ($446.07), Tanzania ($389.83), and Haiti ($219.84). RESULTS: Our results suggest that with a lower Ag threshold, there is a small proportion of simulations where extra rounds are required to reach the target, but this also reduces the need to restart MDA later in the program. For 80% coverage, the lower threshold is cost-effective across all baseline prevalences for India, Tanzania, and Haiti. For 65% MDA coverage, the lower threshold is not cost-effective due to additional MDA rounds, although it increases the probability of local elimination. Valuing the benefits of elimination to align with the GPELF goals, we find that a willingness to pay per capita government expenditure of approximately $1000-$4000 for 1% increase in the probability of local elimination would be required to make a lower threshold cost-effective. CONCLUSIONS: Lower Ag thresholds for stopping MDAs generally mean a higher probability of local elimination, reducing long-term costs and health impacts. However, they may also lead to an increased number of MDA rounds required to reach the lower threshold and, therefore, increased short-term costs. Collectively, our analyses highlight that lower target Ag thresholds have the potential to assist programs in achieving lymphatic filariasis goals.

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.

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.

How Does the Proportion of Never Treatment Influence the Success of Mass Drug Administration Programs for the Elimination of Lymphatic Filariasis?

BACKGROUND: Mass drug administration (MDA) is the cornerstone for the elimination of lymphatic filariasis (LF). The proportion of the population that is never treated (NT) is a crucial determinant of whether this goal is achieved within reasonable time frames. METHODS: Using 2 individual-based stochastic LF transmission models, we assess the maximum permissible level of NT for which the 1% microfilaremia (mf) prevalence threshold can be achieved (with 90% probability) within 10 years under different scenarios of annual MDA coverage, drug combination and transmission setting. RESULTS: For Anopheles-transmission settings, we find that treating 80% of the eligible population annually with ivermectin + albendazole (IA) can achieve the 1% mf prevalence threshold within 10 years of annual treatment when baseline mf prevalence is 10%, as long as NT <10%. Higher proportions of NT are acceptable when more efficacious treatment regimens are used. For Culex-transmission settings with a low (5%) baseline mf prevalence and diethylcarbamazine + albendazole (DA) or ivermectin + diethylcarbamazine + albendazole (IDA) treatment, elimination can be reached if treatment coverage among eligibles is 80% or higher. For 10% baseline mf prevalence, the target can be achieved when the annual coverage is 80% and NT ≤15%. Higher infection prevalence or levels of NT would make achieving the target more difficult. CONCLUSIONS: The proportion of people never treated in MDA programmes for LF can strongly influence the achievement of elimination and the impact of NT is greater in high transmission areas. This study provides a starting point for further development of criteria for the evaluation of NT.

A dynamic game of lymphatic filariasis prevention by voluntary use of insecticide treated nets.

Lymphatic filariasis (LF) has been targeted for elimination as a public health concern by 2030 with a goal to keep the prevalence of LF infections under the 1% threshold. While mass drug administration (MDA) is a primary strategy recommended by WHO, the use of insecticide treated nets (ITN) plays a crucial role as an alternative strategy when MDA cannot be used. In this paper, we use imitation dynamics to incorporate human behavior and voluntary use of ITN into the compartmental epidemiological model of LF transmission. We find the equilibrium states of the dynamics and the ITN usage as it depends on epidemiological parameters and the cost of ITNs. We investigate the conditions under which the voluntary use of ITNs can keep the LF prevalence under the 1% threshold. We found that when the cost of using the ITNs is about 105 smaller than the perceived cost of LF, then the voluntary use of ITNs will eliminate LF as a public health concern. Furthermore, when the ITNs are given away for free, our model predicts that over 80% of the population will use them which would eliminate LF completely in regions where Anopheles are the primary vectors.

An evaluation of mental health integration in the neglected tropical diseases program in Zamfara, North-west Nigeria.

BACKGROUND: Mental health and neglected tropical diseases (NTDs) are critical in healthcare systems, especially in low- and middle-income countries. Several policies are planned or designed by health stakeholders to address the mental health needs of people affected by NTDs. Still, the impact of such policies seems to be of no consequence. METHODS: The GAD-7 and PHQ-9 tools were used to determine the rate of depression and anxiety, respectively, among people affected by skin NTDs (leprosy and lymphatic filariasis [LF]) in Zamfara State, North-west Nigeria. The study also evaluated the barriers to the uptake of mental health services for people affected by skin NTDs in the state. We assessed 48 people affected by NTDs (leprosy, 32; lymphatic filariasis, 16) along with a corresponding 48 people who served as controls in the study. Qualitative interviews were carried out with the participants to elicit the barriers to mental health services for people affected by NTDs. Additionally, 48 selected healthcare workers from the state were assessed for their skills and capacity to offer mental health services. RESULTS: We found anxiety disorder present in 100% of the people living with LF and in 62% of the people living with leprosy. Depression was also found in 56% and 75% of the people living with leprosy and LF, respectively. An assessment of the barriers to the uptake of mental health services reveals that most people with NTDs are constrained by a lack of money to visit hospitals, the fear of stigmatisation and discrimination and long distances to health centres. Regarding the healthcare workers, the skills and capacity to offer mental health services were very low. CONCLUSIONS: We conclude that for mental health services to be integrated into the community health system for people with NTDs, there should be a concerted effort by all stakeholders and the intervention should be context specific instead of generalised. CONTEXTE: La santé mentale et les maladies tropicales négligées (MTN) sont des problématiques centrales dans la santé, en particulier dans les pays à revenu faible ou intermédiaire. Plusieurs politiques sont conçues par les acteurs de la santé publique pour répondre aux besoins de soins en santé mentale pour les personnes touchées par les MTN. Pourtant, le bilan reste mitigé quant à l'efficacité de ces soins. MÉTHODES: Les outils GAD-7 et PHQ-9 ont été utilisés pour déterminer le taux de dépression et d'anxiété chez les personnes atteintes de MTN cutanées (lèpre et filariose lymphatique) dans l'État de Zamfara, au nord-ouest du Nigeria. L'étude a également évalué les obstacles à l'utilisation des services de santé mentale pour les personnes atteintes de MTN cutanées dans l'État. Nous avons évalué 48 personnes atteintes de MTN (lèpre : 32, filariose lymphatique : 16) ainsi que 48 personnes correspondantes qui ont servi de témoins dans l'étude. Des entretiens qualitatifs ont été menés avec les participants afin d'identifier les obstacles aux services de santé mentale pour les personnes atteintes de MTN. En outre, 48 professionnels de la santé sélectionnés dans l'État ont été évalués pour déterminer leurs compétences et leur capacité à offrir des services de santé mentale. RÉSULTATS: Nous avons trouvé des troubles anxieux chez 100% des personnes atteintes de filariose lymphatique et chez 62% des personnes atteintes de lèpre. La dépression touche 56% et 75% des personnes vivant avec la lèpre et la filariose lymphatique respectivement. Une évaluation des obstacles à l'utilisation des services de santé mentale révèle que la plupart des personnes atteintes de MTN sont limitées par le manque d'argent pour se rendre à l'hôpital, la peur de la stigmatisation et de la discrimination, et les longues distances à parcourir pour se rendre dans les centres de santé. Les compétences et les capacités des professionnels de la santé à offrir des services de santé mentale sont très faibles. CONCLUSION: L'efficacité d'un protocole de soins pour les patients atteints de MTN (traitant la pathologie physique et d'éventuelles pathologies psychiatriques associées) nécessite une intégration des services de santé mentale dans le système de santé communautaire. ANTECEDENTES: La salud mental y las enfermedades tropicales desatendidas (ETDs), son fundamentales en los sistemas sanitarios, especialmente en los países de renta baja y media. Las partes interesadas en la sanidad planean o diseñan varias políticas para abordar las necesidades de salud mental de las personas afectadas por ETDs. Sin embargo, el impacto de dichas políticas parece ser nulo. MÉTODOS: Se utilizaron las herramientas GAD-7 y PHQ-9 para determinar la tasa de depresión y ansiedad, respectivamente, entre las personas afectadas por ETDs cutáneas (lepra y filariasis linfática) en el Estado de Zamfara, al noroeste de Nigeria. El estudio también evaluó las barreras para la aceptación de los servicios de salud mental por parte de las personas afectadas por ETDs cutáneas en el Estado. Se evaluó a 48 personas afectadas por ETDs (lepra: 32; filariasis linfática: 16) y a otras 48 que sirvieron de control en el estudio. Se llevaron a cabo entrevistas cualitativas con los participantes para determinar las barreras a los servicios de salud mental para las personas afectadas por ETDs. Además, se evaluaron las habilidades y la capacidad para ofrecer servicios de salud mental de 48 profesionales sanitarios del Estado. RESULTADOS: Encontramos trastorno de ansiedad presente en el 100% de las personas que vivían con filariasis linfática y en el 62% de las personas que vivían con lepra. También se encontró depresión en el 56% y el 75% de las personas que vivían con lepra y filariasis linfática respectivamente. Una evaluación de los obstáculos para la utilización de los servicios de salud mental revela que la mayoría de las personas con ETDs se ven limitadas por la falta de dinero para acudir a los hospitales, el miedo a la estigmatización, la discriminación y las largas distancias hasta los centros sanitarios. Por parte del personal sanitario, los conocimientos y la capacidad para ofrecer servicios de salud mental eran muy escasos. CONCLUSIONES: Para que los servicios de salud mental para personas con ETD se integren en el sistema sanitario comunitario, debe haber una concertación entre todas las partes interesadas y la intervención debe ser específica para cada contexto en lugar de generalizada.

A pilot study to address the mental health of persons living with lymphatic filariasis in Léogâne, Haiti: Implementing a chronic disease self-management program using a stepped-wedge cluster design.

BACKGROUND: Neglected tropical diseases (NTDs) inflict significant comorbid disability on the most vulnerable communities; yet interventions targeting the mental health of affected communities are lacking. A pilot study to assess the effectiveness of a chronic disease self-management program (CDSMP) was introduced to lymphatic filariasis peer support groups in Léogâne, Haiti. METHODS: Using a closed-cohort stepped-wedge cluster trial design, Hope Clubs were assigned into Arm 1 (n=118 members) and Arm 2 (n=92). Household surveys, measuring self-rated health, depression, disease self-efficacy, perceived social support, and quality of life, were conducted at baseline (before CDSMP); midpoint (after Arm 1/before Arm 2 completed CDSMP); and endpoint (after CDSMP). Non-Hope Club member patients (n=74) were evaluated at baseline for comparison. RESULTS: Fifty percent of Hope Club members (Arm 1: 48.3%, Arm 2: 52.2%) screened positive for depression at baseline, compared with 36.5% of non-Hope Club members. No statistically significant differences were found in outcome measures between intervention observation periods. At endpoint, depressive illness reduced to 28.7% (Arm 1) and 27.6% (Arm 2). CONCLUSIONS: The intervention was feasible to integrate into Hope Clubs, showed overall positive effects and reduced depressive symptoms. More studies are needed to evaluate the efficacy of implementing CDSMP in the NTD context. CONTEXTE: Les maladies tropicales négligées (MTN) infligent d'importantes incapacités comorbides aux communautés les plus vulnérables; pourtant, les interventions ciblant la santé mentale des communautés affectées font défaut. Une étude pilote visant à évaluer l'efficacité d'un programme d'autogestion des maladies chroniques (CDSMP) a été introduite dans des groupes de soutien par les pairs pour la filariose lymphatique à Léogâne, en Haïti. MÉTHODES: Dans le cadre d'un essai en grappe à cohorte fermée, les clubs Hope ont été répartis entre le bras 1 (n=118 membres) et le bras 2 (n=92). Des enquêtes auprès des ménages, mesurant l'auto-évaluation de la santé, la dépression, l'auto-efficacité face à la maladie, le soutien social perçu et la qualité de vie, ont été menées au départ (avant le CDSMP), à mi-parcours (après que le bras 1 / avant que le bras 2 ait terminé le CDSMP) et à la fin (après le CDSMP). Les patients non membres du Hope Club (n=74) ont été évalués au début de l'étude à des fins de comparaison. RÉSULTATS: Cinquante pourcent des membres du Hope Club (bras 1 : 48,3%, bras 2 : 52,2%) ont été dépistés positifs pour la dépression au début de l'étude, contre 36,5% des non-membres du Hope Club. Aucune différence statistiquement significative n'a été constatée dans les mesures des résultats entre les périodes d'observation de l'intervention. À la fin de l'étude, la maladie dépressive était réduite à 28,7% (bras 1) et 27,6% (bras 2). CONCLUSIONS: L'intervention a pu être intégrée dans les clubs Hope, elle a montré des effets globalement positifs et a permis de réduire les symptômes dépressifs. D'autres études sont nécessaires pour évaluer l'efficacité de la mise en œuvre du CDSMP dans le contexte des MTD. ANTECEDENTES: Las enfermedades tropicales desatendidas (ETDs) infligen una importante discapacidad comórbida a las comunidades más vulnerables; sin embargo, faltan intervenciones dirigidas a la salud mental de las comunidades afectadas. Se introdujo un estudio piloto para evaluar la eficacia de un programa de autogestión de enfermedades crónicas (CDSMP, por sus siglas en inglés) en grupos de apoyo entre pares de filariasis linfática en Léogâne, Haití. MÉTODOS: Utilizando un diseño de ensayo por conglomerados de cohortes cerradas escalonadas, los Clubes Esperanza fueron asignados al Grupo 1 (n=118 miembros) y al Grupo 2 (n=92). Se realizaron encuestas en los hogares para medir la autoevaluación de la salud, la depresión, la autoeficacia frente a la enfermedad, el apoyo social percibido y la calidad de vida en la línea de base (antes del CDSMP), en el punto medio (después de que el Grupo 1/antes de que el Grupo 2 completara el CDSMP) y en el punto final (después del CDSMP). Los pacientes que no pertenecían al Club Esperanza (n=74) fueron evaluados al inicio del estudio a modo de comparación. RESULTADOS: El 50% de los miembros del Club Esperanza (Grupo 1: 48,3%, Grupo 2: 52,2%) dieron positivo en depresión al inicio del estudio, en comparación con el 36,5% de los no miembros del Club Esperanza. No se encontraron diferencias estadísticamente significativas en las medidas de resultado entre los periodos de observación de la intervención. Al final, la enfermedad depresiva se redujo al 28,7% (Grupo 1) y al 27,6% (Grupo 2). CONCLUSIONES: La intervención fue factible de integrar en los Clubes Esperanza, mostróefectos positivos generales y redujo los síntomas depresivos. Se necesitan más estudios para evaluar la eficacia de la aplicación del CDSMP en el contexto de las ETD.

Motivation-opportunity-ability-behaviour of community members and program implementers towards mass drug administration for lymphatic filariasis elimination in India: a systematic review and implementation priority.

Lymphatic filariasis (LF) is a significant public health issue in India. Despite 10-15 rounds of mass drug administration (MDA) in India, the global LF elimination target of 2030 appears challenging. To strengthen the program, community and provider perspectives on ways to bridge a gap in MDA are needed. Through the motivation-opportunity-ability-behaviour (MOAB) lens, we systematically reviewed the facilitators and barriers encountered in LF elimination in India. We followed Preferred Reporting Items for Systematic Review and Meta-Analysis guidelines. We searched PubMed, Embase, ProQuest and Google Scholar databases to explore factors related to MDA program implementation in India through 30 June 2021. We analysed the data using a thematic framework. We identified 576 studies; of these, 20 studies were included. This review revealed that the public health system for distributing MDA drugs in India created a better enabling environment, including zero out-of-pocket expenditure, door-step distribution of medicines and ample capacity-building training and follow-up. However, community members were unaware of the rationale for drug consumption, leading to a gap in drug distribution and consumption. Motivation is required among community members, which suggests capacity-building training for service providers to counsel the community.

Immunomodulation of streptozotocin induced Type 1 diabetes mellitus in mouse model by Macrophage migration inhibitory factor-2 (MIF-2) homologue of human lymphatic filarial parasite, Wuchereria bancrofti.

Helminth parasites modulate the host immune system to ensure a long-lasting asymptomatic form of infection generally, mediated by the secretion of immunomodulatory molecules and one such molecule is a homologue of human host cytokine, Macrophage migratory Inhibitory Factor (hMIF). In this study, we sought to understand the role of homologue of hMIF from the lymphatic filarial parasite, Wuchereria bancrofti (Wba-MIF2), in the immunomodulation of the Streptozotocin (STZ)-induced Type1 Diabetes Mellitus (T1DM) animal model. Full-length recombinant Wba-MIF2 was expressed and found to have both oxidoreductase and tautomerase activities. Wba-MIF2 recombinant protein was treated to STZ induced T1DM animals, and after 5 weeks pro-inflammatory (IL-1, IL-2, IL-6, TNF-α, IFN-γ) and anti-inflammatory (IL-4, IL-10) cytokines and gene expressions were determined in sera samples and spleen respectively. Pro-inflammatory and anti-inflammatory cytokine levels were significantly (p<0.05) up-regulated and down-regulated respectively, in the STZ-T1DM animals, as compared to treated groups. Histopathology showed macrophage infiltration and greater damage of islets of beta cells in the pancreatic tissue of STZ-T1DM animals, than Wba-MIF2 treated STZ-T1DM animals. The present study clearly showed the potential of Wba-MIF2 as an immunomodulatory molecule, which could modulate the host immune system in the STZ-T1DM mice model from a pro-inflammatory to anti-inflammatory milieu.

A Landscape on Lymphatic Filariasis with its Effects and Recent Advanced Treatments.

Lymphatic filariasis is an infection caused by parasites that poses a significant health, social, and economic burden, affecting a vast population that exceeds 120 million individuals globally. The Etiology of the infection is attributed to three nematode parasites, namely Wuchereria bancrofti, B. timori, and Brugia malayi, as well as which are phylogenetically related. These parasites are transmitted to humans via mosquitoes belonging to the Anopheles, Aedes genera, and Culex. As per the estimation provided by the WHO, the current number of individuals infected with filariasis stands at approximately 120 million across 81 countries. Furthermore, it is estimated that around 1.34 billion individuals reside in regions that are endemic to filariasis, thereby putting them at risk of contracting the disease. Different synthetic drugs such as Ivermectin, Doxycycline, Albendazole, and Suramin are used in the treatment. Some natural plants are Azadirachta indica, Tinospora cordifolia, Zingiber officinal, as well as, some marine sources are also included for better treatment. We also touch briefly on a few additional filarial diseases. Although there are only a few medications available to treat filariasis, their frequent usage may result in drug resistance. Furthermore, there is no effective vaccination for the treatment of filariasis. Due to these restrictions, it has been crucial to create new anti-filarial medications, which motivates researchers to find novel pharmaceuticals with anti-filarial action. In this article, we examine the latest achievements in the anti-filarial area, including the many forms of filariasis and their historical contexts, elimination programmes, various therapeutic classes (both synthetic and natural), investigated product-derived targets as well as clinical investigations.

Detection of Wuchereria bancrofti DNA in wild caught vector and non-vector mosquitoes: implications for elimination of lymphatic filariasis.

BACKGROUND: Transmission Assessment Survey (TAS) is the WHO recommended method used for decision-making to stop or continue the MDA in lymphatic filariasis (LF) elimination programme. The WHO has also recommended Molecular Xenomonitoring (MX) of LF infection in vectors as an adjunct tool in settings under post-MDA or validation period. Screening of non-vectors by MX in post-MDA / validation settings could be useful to prevent a resurgence of LF infection, as there might be low abundance of vectors, especially in some seasons. In this study, we investigated the presence of LF infection in non-vectors in an area endemic for LF and has undergone many rounds of annual MDA with two drugs (Diethylcarbamazine and Albendazole, DA) and two rounds of triple drug regimens (Ivermectin + DA). METHODS AND RESULTS: Mosquitoes were collected from selected villages of Yadgir district in Karnataka state, India, during 2019. A total of 680 female mosquitoes were collected, identified morphologically by species and separated as pools. The female mosquitoes belonging to 3 species viz., Anopheles subpictus, Culex gelidus and Culex quinquefaciatus were separated, pooled, and the DNA extracted using less expensive method and followed by LDR based real-time PCR assay for detecting Wuchereria bancrofti infection in vector as well as non-vector mosquitoes. One pool out of 6 pools of An. subpictus, 2 pools out of 6 pools of Cx. gelidus, and 4 pools out of 8 pools of Cx. quinquefaciatus were found to be positive for W. bancrofti infection by RT-PCR. The infection rate in vectors and non-vectors was found to be 1.8% (95% CI: 0.5-4.2%) and 0.9% (95% CI: 0.2-2.3%), respectively. CONCLUSIONS: Our study showed that non-vectors also harbour W. bancrofti, thus opening an opportunity of using these mosquitoes as surrogate vectors for assessing risk of transmission to humans in LF endemic and post MDA areas.

Combinations of the azaquinazoline anti-Wolbachia agent, AWZ1066S, with benzimidazole anthelmintics synergise to mediate sub-seven-day sterilising and curative efficacies in experimental models of filariasis.

Lymphatic filariasis and onchocerciasis are two major neglected tropical diseases that are responsible for causing severe disability in 50 million people worldwide, whilst veterinary filariasis (heartworm) is a potentially lethal parasitic infection of companion animals. There is an urgent need for safe, short-course curative (macrofilaricidal) drugs to eliminate these debilitating parasite infections. We investigated combination treatments of the novel anti-Wolbachia azaquinazoline small molecule, AWZ1066S, with benzimidazole drugs (albendazole or oxfendazole) in up to four different rodent filariasis infection models: Brugia malayi-CB.17 SCID mice, B. malayi-Mongolian gerbils, B. pahangi-Mongolian gerbils, and Litomosoides sigmodontis-Mongolian gerbils. Combination treatments synergised to elicit threshold (>90%) Wolbachia depletion from female worms in 5 days of treatment, using 2-fold lower dose-exposures of AWZ1066S than monotherapy. Short-course lowered dose AWZ1066S-albendazole combination treatments also delivered partial adulticidal activities and/or long-lasting inhibition of embryogenesis, resulting in complete transmission blockade in B. pahangi and L. sigmodontis gerbil models. We determined that short-course AWZ1066S-albendazole co-treatment significantly augmented the depletion of Wolbachia populations within both germline and hypodermal tissues of B. malayi female worms and in hypodermal tissues in male worms, indicating that anti-Wolbachia synergy is not limited to targeting female embryonic tissues. Our data provides pre-clinical proof-of-concept that sub-seven-day combinations of rapid-acting novel anti-Wolbachia agents with benzimidazole anthelmintics are a promising curative and transmission-blocking drug treatment strategy for filarial diseases of medical and veterinary importance.

Factors influencing implementation of mass drug administration for lymphatic filariasis elimination: a mixed-method study in Odisha, India.

Background: Lymphatic filariasis (LF) persists as a public health problem in India. Despite more than ten rounds of mass drug administration (MDA), LF continues to be endemic in the Dhenkanal district of Odisha. Hence, we assessed the coverage and compliance of the MDA program and explored the factors affecting it in the Dhenkanal district. Methods: An explanatory mixed-method study was conducted, wherein for the quantitative survey, 552 participants aged 2 years and above were recruited following a multistage cluster random sampling during February 2022. In-depth interviews were conducted among purposively selected key stakeholders and program implementers. Descriptive statistics were used to report coverage and compliance, along with a 95% confidence interval. Qualitative data were analyzed using a thematic approach. Results: We observed coverage of 99.28% and compliance of 85.87% for MDA drugs. Supervised drug administration proved to be a major pillar in increasing compliance. There was difficulty in administering drugs in urban areas due to gated societies, the absence of individuals during the day, and the perspective toward healthcare providers. Participants reported a lack of confidence in drug distributors and a fear of side effects as major causes for non-compliance. Conclusion: There is a need to strengthen MDA, especially in urban areas. An urban-specific strategy, along with surveillance, behavioral change communication, and the involvement of multi-disciplinary teams, is required.

Zambia: A Narrative Review of Success and Challenges in Lymphatic Filariasis Elimination.

The establishment of the Global Programme to Eliminate Lymphatic Filariasis (GPELF) to stop the transmission of infection has significantly reduced the incidence of lymphatic filariasis, a debilitating mosquito-borne neglected tropical disease. The primary strategies that have been employed include mass drug administration (MDA) of anthelminthics and morbidity management and disability prevention (MMDP). While some countries have been able to reach elimination status in Africa, there is still active transmission of LF in Zambia. The nematode responsible for the disease is Wuchereria bancrofti, which is transmitted by Anopheles mosquitoes. To alleviate the suffering of those infected by the disease, the Zambian Ministry of Health launched a program to eliminate LF as a public health problem in 2003. This project reviewed the efforts to achieve the elimination of LF in Zambia, past and present government policies, and the anticipated challenges. MDAs have been conducted since 2014 and coverage has been between 87% and 92%. Zambia has now moved towards pre-transmission assessment surveys (PRETAS) and transmission assessment surveys (TAS). MMDP is a major priority and planned to be conducted between 2022 and 2026. COVID-19 presented a new challenge in the control of LF, while climate change, immigration, co-infections, and funding limitations will complicate further progress.

Five years of post-validation surveillance of lymphatic filariasis in Thailand.

BACKGROUND: The World Health Organization (WHO) validated Thailand in 2017 as having eliminated lymphatic filariasis (LF) as a public health problem with recommendations for continued surveillance. This article describes measures and progress made in Thailand with post-validation surveillance (PVS) of LF from 2018 until 2022. METHODS: The implementation unit (IU) is a sub-village in 11 former LF endemic provinces. Human blood surveys are targeted in 10% of IUs each year. In Wuchereria bancrofti areas, filaria antigen test strips (FTS) are used, and in Brugia malayi areas, antibody test kits (Filaria DIAG RAPID) are used. Positive cases are confirmed by thick blood film (TBF) and polymerase chain reaction (PCR). Vector surveys for mosquito species identification and dissection for microfilaria (Mf)/filarial larvae are done in 1% of IUs where human blood surveys are conducted. Human blood surveys using FTS are conducted among migrants in five provinces. Surveillance of cats is done in areas that previously recorded > 1.0% Mf rate among cats. Morbidity management and disability prevention (MMDP) are done every 2 years in LF-endemic areas where chronic disease patients reside. RESULTS: From 2018 to 2022, in a total of 357 IUs in 11 provinces, human blood surveys were conducted in 145 IUs (41%) with an average population coverage of 81%. A total of 22,468 FTS and 27,741 FilariaDIAG RAPID were performed. 27 cases were detected: 3 cases of W. bancrofti in Kanchanaburi province and 24 cases of B. malayi in Narathiwat province. 4 cases of W. bancrofti were detected in two provinces through routine public health surveillance. Vector surveys in 47 IUs detected B. malayi Mf filarial larvae only in Narathiwat province. Chronic LF patients reduced from 114 in 2017 to 76 in 2022. Surveys among 7633 unregistered migrants yielded 12 cases of W. bancrofti. Mf rate among cats in Narathiwat province declined from 1.9% in 2018 to 0.7% in 2022. MMDP assessments revealed gaps in healthcare provider's management of chronic cases due to staff turnover. CONCLUSIONS: In 2022, after 5 years of PVS, Thailand re-surveyed 41% of its previously endemic IUs and demonstrated ongoing transmission in only one province of Narathiwat, where Mf prevalence is below the WHO provisional transmission threshold of 1%. This study highlights the importance of continued disease surveillance measures and vigilance among health care providers in LF receptive areas.

Giant Scrotal Lymphoedema: A Case Series.

Giant scrotal lymphoedema is a rare condition caused by obstruction, aplasia, or hypoplasia of lymphatic vessels draining the external genitalia. While this condition can be congenital or acquired, the most common acquired cause of such lymphatic obstruction worldwide is lymphatic filariasis (LF). We present a case series analysis of three patients of giant scrotal lymphoedema who were successfully treated for the condition in the Department of General Surgery, King George's Medical University (KGMU), Lucknow, with satisfactory post-operative recovery and minimal recurrence. The first patient was a 45-year-old who had been living with the condition for 10 years, and the resected scrotal tissue weighed 35 kg. The second patient was a 45-year-old who was diagnosed with filariasis five years back before the condition set in, and the resected scrotal tissue weighed 32 kg. The third patient was a 22-year-old young man who had been diagnosed with the condition 10 years back, and the resected scrotal tissue weighed 25 kg. Proper pre-operative evaluation was conducted in all three patients to establish the diagnosis of scrotal lymphoedema. The urethral catheterisation was conducted, which additionally helped to identify penile tissue intraoperatively. Careful exploration of scrotal tissue was conducted along with delineation of the penis from scrotal oedema. The surgical approach involved debulking scrotal lymphoedema with the reconstruction of scrotal skin while preserving penile tissue. Patients with giant scrotal lymphoedema face the social stigma that creates physical disability. Hence, they end up seeking medical help from tertiary care centres after the disease has reached advanced stages and fibrosis has set in. However, single-stage debulking, along with reconstructive surgery (referred to as reduction scrotoplasty), yields promising results even in cases of very bulky scrotal lymphoedema, weighing up to 35 kg, as per our study.

Entomological surveillance reveals transmission of malaria but not lymphatic filariasis in two communities in North-West Nigeria.

Malaria and lymphatic filariasis (LF) are two serious public health challenges in sub-Saharan Africa, and both diseases are transmitted by Anopheles mosquitoes. Successful control of both diseases requires detailed information on transmission dynamics; thus, this study investigated malaria and LF transmission indices in two (2) communities (Jidawa and Kargo) in North-West Nigeria. Anopheles mosquitoes were sampled from twenty-five (25) randomly selected houses from each of the two communities using pyrethrum spray collection (PSC). The samples were identified morphologically and molecularly characterised using polymerase chain reaction (PCR). Human biting rate (HBR), indoor resting density (IRD), sporozoite rate (SR) and entomological inoculation rate (EIR) were calculated using standard formulae. The thorax region of the collected samples were dissected and smeared; then, Plasmodium and Wuchereria bancrofti parasites were identified using microscopy. A total of 2417 Anopheles mosquitoes were collected, and all were identified morphologically as An. gambiae s.l. Further molecular identification of sibling species revealed that An. gambiae and An. arabiensis were the only sibling species present. A total of 818 Anopheles mosquitoes were screened for Plasmodium and Wuchereria bancrofti parasites. A total of 180 samples were positive for Plasmodium parasites (Jidawa = 151; Kargo = 29), and none was positive for W. bancrofti (0%). Result of entomological indices for malaria transmission showed that indoor resting density was higher in Jidawa (10 mosquitoes/room/night) while human biting rate (2.07 bites/person/night), sporozoite rate (29.3%) and entomological inoculation rate (0.61) were higher in Kargo. In total, 35.2% of the samples were blood-fed while 67.4% were parous. There is active transmission of malaria in the two communities but not LF, suggesting the effectiveness of mass drug administration for LF. Concerted efforts should be focused on malaria control as transmission of the disease persists.