How Does Treatment Coverage and Proportion Never Treated Influence the Success of Schistosoma mansoni Elimination as a Public Health Problem by 2030?

BACKGROUND: The 2030 target for schistosomiasis is elimination as a public health problem (EPHP), achieved when the prevalence of heavy-intensity infection among school-aged children (SAC) reduces to <1%. To achieve this, the new World Health Organization guidelines recommend a broader target of population to include pre-SAC and adults. However, the probability of achieving EPHP should be expected to depend on patterns in repeated uptake of mass drug administration by individuals. METHODS: We employed 2 individual-based stochastic models to evaluate the impact of school-based and community-wide treatment and calculated the number of rounds required to achieve EPHP for Schistosoma mansoni by considering various levels of the population never treated (NT). We also considered 2 age-intensity profiles, corresponding to a low and high burden of infection in adults. RESULTS: The number of rounds needed to achieve this target depends on the baseline prevalence and the coverage used. For low- and moderate-transmission areas, EPHP can be achieved within 7 years if NT ≤10% and NT <5%, respectively. In high-transmission areas, community-wide treatment with NT <1% is required to achieve EPHP. CONCLUSIONS: The higher the intensity of transmission, and the lower the treatment coverage, the lower the acceptable value of NT becomes. Using more efficacious treatment regimens would permit NT values to be marginally higher. A balance between target treatment coverage and NT values may be an adequate treatment strategy depending on the epidemiological setting, but striving to increase coverage and/or minimize NT can shorten program duration.

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.

Patterns of soil-transmitted helminth aggregation in the human host population after several years of intensive mass drug administration.

BACKGROUND: Community-wide mass drug administration (cMDA) is known as an effective, albeit costly, control strategy for soil-transmitted helminth (STH) parasites. A better understanding of STH aggregation after many rounds of cMDA could help shape more cost-effective policies. METHODS: This analysis uses data from the Geshiyaro project, aiming to break STH transmission by cMDA and water, sanitation and hygiene interventions. Ascaris lumbricoides infection prevalence is derived from egg count data and parasite aggregation is obtained by fitting a negative binomial distribution to the frequency distribution of faecal egg counts. RESULTS: The relationship between parasite dispersion and infection prevalence is approximately linear. Parasite aggregation increases as infection prevalence decreases. CONCLUSIONS: A minority of individuals carry most parasites as prevalence decreases in the community. These individuals could be selectively targeted for repeated treatment.

How important is the spatial movement of people in attempts to eliminate the transmission of human helminth infections by mass drug administration?

Human mobility contributes to the spatial dynamics of many infectious diseases, and understanding these dynamics helps us to determine the most effective ways to intervene and plan surveillance. In this paper, we describe a novel transmission model for the spatial dynamics of hookworm, a parasitic worm which is a common infection across sub-Saharan Africa, East Asia and the Pacific islands. We fit our model, with and without mobility, to data obtained from a sub-county in Kenya, and validate the model's predictions against the decline in prevalence observed over the course of a clustered randomized control trial evaluating methods of administering mass chemotherapy. We find that our model which incorporates human mobility is able to reproduce the observed patterns in decline of prevalence during the TUMIKIA trial, and additionally, that the widespread bounce-back of infection may be possible over many years, depending on the rates of people movement between villages. The results have important implications for the design of mass chemotherapy programmes for the elimination of human helminth transmission. This article is part of the theme issue 'Challenges and opportunities in the fight against neglected tropical diseases: a decade from the London Declaration on NTDs'.

Individual longitudinal compliance to neglected tropical disease mass drug administration programmes, a systematic review.

Repeated distribution of preventative chemotherapy (PC) by mass drug administration forms the mainstay of transmission control for five of the 20 recognised neglected tropical diseases (NTDs); soil-transmitted helminths, schistosomiasis, lymphatic filariasis, onchocerciasis and trachoma. The efficiency of such programmes is reliant upon participants swallowing the offered treatment consistently at each round. This is measured by compliance, defined as the proportion of eligible participants swallowing treatment. Individually linked longitudinal compliance data is important for assessing the potential impact of MDA-based control programmes, yet this accurate monitoring is rarely implemented in those for NTDs. Longitudinal compliance data reported by control programmes globally for the five (PC)-NTDs since 2016 is examined, focusing on key associations of compliance with age and gender. PubMed and Web of Science was searched in January 2022 for articles written in English and Spanish, and the subsequent extraction adhered to PRISMA guidelines. Study title screening was aided by Rayyan, a machine learning software package. Studies were considered for inclusion if primary compliance data was recorded for more than one time point, in a population larger than 100 participants. All data analysis was conducted in R. A total of 89 studies were identified containing compliance data, 57 were longitudinal studies, of which 25 reported individually linked data reported by varying methods. The association of increasing age with the degree of systematic treatment was commonly reported. The review is limited by the paucity of data published on this topic. The varying and overlapping terminologies used to describe coverage (receiving treatment) and compliance (swallowing treatment) is reviewed. Consequently, it is recommended that WHO considers clearly defining the terms for coverage, compliance, and longitudinal compliance which are currently contradictory across their NTD treatment guidelines. This review is registered with PROSPERO (number: CRD42022301991).

The observed relationship between the degree of parasite aggregation and the prevalence of infection within human host populations for soil-transmitted helminth and schistosome infections.

BACKGROUND: Soil-transmitted helminths (STH) and schistosome parasites are highly aggregated within the human population. The probability distribution of worms per person is described well by the negative binomial probability distribution with aggregation parameter, k, which varies inversely with parasite clustering. The relationship between k and prevalence in defined populations subject to mass drug administration is not well understood. METHODS AND RESULTS: We use statistical methods to estimate k using two large independent datasets for STH and schistosome infections from India and Niger, respectively, both of which demonstrate increased aggregation of parasites in a few hosts, as the prevalence of infections declines across the dataset. CONCLUSIONS: A greater attention needs to be given in monitoring and evaluation programmes to find and treat the remaining aggregates of parasites.

Commentary on the use of the reproduction number R during the COVID-19 pandemic.

Since the beginning of the COVID-19 pandemic, the reproduction number [Formula: see text] has become a popular epidemiological metric used to communicate the state of the epidemic. At its most basic, [Formula: see text] is defined as the average number of secondary infections caused by one primary infected individual. [Formula: see text] seems convenient, because the epidemic is expanding if [Formula: see text] and contracting if [Formula: see text]. The magnitude of [Formula: see text] indicates by how much transmission needs to be reduced to control the epidemic. Using [Formula: see text] in a naïve way can cause new problems. The reasons for this are threefold: (1) There is not just one definition of [Formula: see text] but many, and the precise definition of [Formula: see text] affects both its estimated value and how it should be interpreted. (2) Even with a particular clearly defined [Formula: see text], there may be different statistical methods used to estimate its value, and the choice of method will affect the estimate. (3) The availability and type of data used to estimate [Formula: see text] vary, and it is not always clear what data should be included in the estimation. In this review, we discuss when [Formula: see text] is useful, when it may be of use but needs to be interpreted with care, and when it may be an inappropriate indicator of the progress of the epidemic. We also argue that careful definition of [Formula: see text], and the data and methods used to estimate it, can make [Formula: see text] a more useful metric for future management of the epidemic.

Probability distributions of helminth parasite burdens within the human host population following repeated rounds of mass drug administration and their impact on the transmission breakpoint.

The existence of multiple stable equilibria in models of parasitic helminth transmission was a ground-breaking discovery over 30 years ago. An implication of this discovery, that there is a level of infection below which transmission cannot self-sustain called the transmission breakpoint, has in part motivated the push towards the elimination of many human diseases caused by the multiple species of helminth worldwide. In the absence of vaccines, the predominant method in this push towards elimination is to repeatedly administer endemic populations with anthelmintic drugs, over several treatment rounds, in what has become to be known as mass drug administration (MDA). MDA will inevitably alter the distribution of parasite burdens among hosts from the baseline distribution, and significantly, the location of the transmission breakpoint is known to be dependent on the level of aggregation of this distribution-for a given mean worm burden, more highly aggregated distributions where fewer individuals harbour most of the burden, will have a lower transmission breakpoint. In this paper, we employ a probabilistic analysis of the changes to the distribution of burdens in a population undergoing MDA, and simple approximations, to determine how key aspects of the programmes (including compliance, drug efficacy and treatment coverage) affect the location of the transmission breakpoint. We find that individual compliance to treatment, which determines the number of times an individual participates in mass drug administration programmes, is key to the location of the breakpoint, indicating the vital importance to ensure that people are not routinely missed in these programmes.

SCHISTOX: An individual based model for the epidemiology and control of schistosomiasis.

A stochastic individual based model, SCHISTOX, has been developed for the study of schistosome transmission dynamics and the impact of control by mass drug administration. More novel aspects that can be investigated include individual level adherence and access to treatment, multiple communities, human sex population dynamics, and implementation of a potential vaccine. Many of the model parameters have been estimated within previous studies and have been shown to vary between communities, such as the age-specific contact rates governing the age profiles of infection. However, uncertainty remains as there are wide ranges for certain parameter values and a few remain relatively unknown. We analyse the model dynamics by parameterizing it with published parameter values. We also discuss the development of SCHISTOX in the form of a publicly available open-source GitHub repository. The next key development stage involves validating the model by calibrating to epidemiological data.

Defining a prevalence level to describe the elimination of Lymphatic Filariasis (LF) transmission and designing monitoring & evaluating (M&E) programmes post the cessation of mass drug administration (MDA).

The global decline in prevalence of lymphatic filariasis has been one of the major successes of the WHO's NTD programme. The recommended strategy of intensive, community-wide mass drug administration, aims to break localised transmission by either reducing the prevalence of microfilaria positive infections to below 1%, or antigen positive infections to below 2%. After the threshold is reached, and mass drug administration is stopped, geographically defined evaluation units must pass Transmission Assessment Surveys to demonstrate that transmission has been interrupted. In this study, we use an empirically parameterised stochastic transmission model to investigate the appropriateness of 1% microfilaria-positive prevalence as a stopping threshold, and statistically evaluate how well various monitoring prevalence-thresholds predict elimination or disease resurgence in the future by calculating their predictive value. Our results support the 1% filaremia prevalence target as appropriate stopping criteria. However, because at low prevalence-levels random events dominate the transmission dynamics, we find single prevalence measurements have poor predictive power for predicting resurgence, which suggests alternative criteria for restarting MDA may be beneficial.

Policy implications of the potential use of a novel vaccine to prevent infection with Schistosoma mansoni with or without mass drug administration.

Schistosomiasis is one of the most important neglected tropical diseases (NTDs) affecting millions of people in 79 different countries. The World Health Organization (WHO) has specified two control goals to be achieved by 2020 and 2025 - morbidity control and elimination as a public health problem (EPHP). Mass drug administration (MDA) is the main method for schistosomiasis control but it has sometimes proved difficult to both secure adequate supplies of the most efficacious drug praziquantel to treat the millions infected either annually or biannually, and to achieve high treatment coverage in targeted communities in regions of endemic infection. The development of alternative control methods remains a priority. In this paper, using stochastic individual-based models, we analyze whether the addition of a novel vaccine alone or in combination with drug treatment, is a more effective control strategy, in terms of achieving the WHO goals, as well as the time and costs to achieve these goals when compared to MDA alone. The key objective of our analyses is to help facilitate decision making for moving a promising candidate vaccine through the phase I, II and III trials in humans to a final product for use in resource poor settings. We find that in low to moderate transmission settings, both vaccination and MDA are highly likely to achieve the WHO goals within 15 years and are likely to be cost-effective. In high transmission settings, MDA alone is unable to achieve the goals, whereas vaccination is able to achieve both goals in combination with MDA. In these settings Vaccination is cost-effective, even for short duration vaccines, so long as vaccination costs up to US$7.60 per full course of vaccination. The public health value of the vaccine depends on the duration of vaccine protection, the baseline prevalence prior to vaccination and the WHO goal.

Vaccination or mass drug administration against schistosomiasis: a hypothetical cost-effectiveness modelling comparison.

BACKGROUND: Schistosomiasis is a neglected tropical disease, targeted by the World Health Organization for reduction in morbidity by 2020. It is caused by parasitic flukes that spread through contamination of local water sources. Traditional control focuses on mass drug administration, which kills the majority of adult worms, targeted at school-aged children. However, these drugs do not confer long-term protection and there are concerns over the emergence of drug resistance. The development of a vaccine against schistosomiasis opens the potential for control methods that could generate long-lasting population-level immunity if they are cost-effective. METHODS: Using an individual-based transmission model, matched to epidemiological data, we compared the cost-effectiveness of a range of vaccination programmes against mass drug administration, across three transmission settings. Health benefit was measured by calculating the heavy-intensity infection years averted by each intervention, while vaccine costs were assessed against robust estimates for the costs of mass drug administration obtained from data. We also calculated a critical vaccination cost, a cost beyond which vaccination might not be economically favorable, by benchmarking the cost-effectiveness of potential vaccines against the cost-effectiveness of mass drug administration, and examined the effect of different vaccine protection durations. RESULTS: We found that sufficiently low-priced vaccines can be more cost-effective than traditional drugs in high prevalence settings, and can lead to a greater reduction in morbidity over shorter time-scales. MDA or vaccination programmes that target the whole community generate the most health benefits, but are generally less cost-effective than those targeting children, due to lower prevalence of schistosomiasis in adults. CONCLUSIONS: The ultimate cost-effectiveness of vaccination will be highly dependent on multiple vaccine characteristics, such as the efficacy, cost, safety and duration of protection, as well as the subset of population targeted for vaccination. However, our results indicate that if a vaccine could be developed with reasonable characteristics and for a sufficiently low cost, then vaccination programmes can be a highly cost-effective method of controlling schistosomiasis in high-transmission areas. The population-level immunity generated by vaccination will also inevitably improve the chances of interrupting transmission of the disease, which is the long-term epidemiological goal.