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New approaches to characterise Schistosoma mansoni infections persisting despite mass drug administration

Periodic Reporting for period 2 - SCHISTO_PERSIST (New approaches to characterise Schistosoma mansoni infections persisting despite mass drug administration)

Reporting period: 2017-10-01 to 2019-03-31

Neglected tropical diseases (NTDs) affect >1.4 billion people and cause a higher global disease burden than HIV/AIDS. Several NTD control programmes use mass drug administration (MDA) as their main strategy. Yet many communities continue to harbour heavy infections. Schistosomiasis, second only to malaria amongst parasitic diseases in terms of its socio-economic importance, infects >240 million people worldwide. In 2003, Uganda implemented praziquantel mass drug administration (MDA) for schistosomiasis. MDA imposes intensive selective pressures that raise drug-resistance concerns. In a Ugandan district we have worked in since 2004 we now observe heavier infections than at baseline, with similar ‘hotspots’ being reported across Africa. There are no viable alternatives to praziquantel and thus emerging resistance would have major implications for the control programme.

Efforts to monitor drug efficacy are impeded by an inability to differentiate between surviving worms and reinfections, and a lack of a quantifiable in vitro measure without laboratory mammals. As a consequence, the relative contribution of parasite (e.g. drug resistance, hybrid species) and host (e.g. immunology, pharmacokinetics) factors to transmission is unknown. To reduce transmission in hotspots it will be important to also quantify the risk of reinfection from untreated individuals.

Our key objectives are therefore to use innovative and interdisciplinary approaches to pioneer new diagnostic methods, optimise drug-efficacy monitoring protocols, validate drug-resistance phenotypic markers, and identify key factors that contribute to Schistosoma mansoni hotspots despite MDA.

Specifically we address five questions, each with individual objectives listed below:

I. What is the best way to monitor schistosome infections and drug efficacy?
a) Deploy and validate point-of-care DNA-diagnostic for schistosomes, other NTDs, and malaria.
b) Utilise specific estimates of parasite egg, antigen and DNA clearance post treatment and evaluate each as markers of in vivo drug efficacy.
c) Differentiate surviving and newly-acquired worms using sibship analysis.

II. Has drug resistance been selected for?
a) Identify individuals not cured by repeated treatments using new optimised monitoring protocols.
b) Develop quantifiable in vitro drug-resistance test by adapting imaging technology.
c) Link in vitro and in vivo drug-resistance phenotypes to parasite genotypes.

III. What is the potential for the spread of drug resistance?
a) Establish vital data on parasite population structure and levels of gene flow.
b) Parameterise novel local, national and international human migration models.
c) Characterise the potential risk of bi-annual treatment using interdisciplinary mathematical models.

IV. What other factors drive transmission?
a) Measure MDA coverage and infection prevalence to test the newly-reported potential risk of low MDA coverage resulting in higher bounce-back infection levels.
b) Characterise the relative contributions of untreated groups to reinfection of treated children.
c) Characterise the contribution of individuals with high parasite intensities to reinfection of children.

V. What other factors affect parasite clearance?
a) Establish the influence of host factors such as immunology and pharmacokinetics on low cure rates.
b) Assess the level of ‘resistant’ S. mansoni parasites that are potentially hybrid parasites.

We aim for our data to inform control strategies locally and ultimately assist in reducing the global burden of schistosomiasis.
In 2017 and 2018, the SCHISTO_PERSIST team has successfully conducted seven major field programmes in Mayuge District, Uganda to address the objectives of 'New approaches to characterise Schistosoma mansoni infections persisting despite mass drug administration (SCHISTO_PERSIST)'. These field programmes targeted several objectives outlined in the original research ethics applications with field and laboratory efforts ongoing.

Samples have been collected from school-aged children, pre-school aged children and adults from infected communities. Data about infection levels, treatment history and illness symptoms have been collected along with blood, urine and stool samples collected for drug absorption, microbiome and immunology studies. At all time points parasites, themselves, have been collected for genetic analyses.

Key results from surveys indicate that people who are often labelled as refusing the drug treatment (systematic non-compliers) are actually more likely to have not been offered the drug, meaning that outreach and improved sensitization campaigns can improve drug uptake, rather than targeted education programmes to change people’s views on the treatment. Infection data show that children are rapidly reinfected after treatment, but that adults if they swallow the treatments, tend to keep their infections lower for longer. Most adults enrolled in our study however had never been treated before, highlighting that making the effort to reach these adults, might reduce long term illness in them, as well as reduce the chance of them reinfecting the children, who still show susceptibility to infection.

Infection data collected during this ERC are being used in mathematical models to help us understand why these Ugandan communities are not clearing as expected with repeated treatments. These models highlight the limitations of the current diagnostics and the importance of developing improved ones and using genetics to fully understand what is happening to the parasites when people are taking the treatment drug.

Many of the field samples have now been collected and the laboratory analyses continues.

Academic dissemination:
In the first 30 months of this project, my team's research has contributed to eight published papers linked to this project, helping us to understand schistosomiasis and intestinal worms in these heavily infected communities.

In addition to the published journal articles, the SCHISTO_PERSIST team have presented their findings at several international conferences. These include the British Society for Parasitology, the American Society for Tropical Medicine and Hygiene, Evolution, and the International Society for Neglected Tropical Diseases.

Findings have also been presented and discussed at smaller meetings, with direct access to global health policy makers, such as at the World Health Organization, at expert meetings organised by the Bill and Melinda Gates Foundation, FIND diagnostics, the Global Schistosomiasis Alliance and the Coalition for Neglected Tropical Diseases Meetings for example.

Non academic dissemination projects include:

In Uganda in March 2018, Acting for Health ran a pilot programme in a fishing community heavily affected with schistosomiasis (Bugoto Village in Mayuge District on the north shore of Lake Victoria) linked to the research carried out on this ERC project and run in collaboration with Uganda’s Vector Control Division. Acting for Health brought together key members of the community and healthcare system to understand and address the community's main barriers to schistosomiasis control (lack of treatment uptake, unsafe water contact, inadequate sanitation, false beliefs about the disease and infection, ...). A series of workshops translated the stakeholders' voices into characters and sketches, performed by the community in front of an audience from across the village. This resulted in strong engagement by the local community, an improved understanding of the t
We are undertaking innovative steps to understand the biological aspects of why schistosomiasis remains such a huge problem across several communities in Uganda. We are using the latest genetic techniques to develop protocol for analysing family relationships in the parasites to see if they are siblings or half siblings. This will help us understand the effect of hte drug and measure how successful the treatments have been by seeing if the eggs excreted post treatment are from new infections or worms whihc have survived treatment.

We have unprecedented follow up data from primary school children and have analysed these with novel mathematical methods.

As the project progresses, the knowledge we gain on additional factors driving transmission and reducing drug efficacy may identify simple actions to increase treatment success, inform control programmes on drug-resistance risks, and advise national and international policy makers on how best to control this debilitating disease. Most research findings will be directly transferable to other countries and other Neglected Tropical Diseases.
Lush green fields of Uganda
Mud and reed toilet in Uganda
Mending the fishing nets in infected communities
Typical village in Uganda where we work