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

Periodic Reporting for period 3 - SCHISTO_PERSIST (New approaches to characterise Schistosoma mansoni infections persisting despite mass drug administration)

Reporting period: 2019-04-01 to 2020-09-30

Over 240 million people are infected with schistosomiasis worldwide. In 2003, Uganda implemented praziquantel mass drug administration (MDA) but 'hotspots’ of high transmission remain. There are no viable alternatives to praziquantel and emerging resistance would have major implications for control programmes.

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 interdisciplinary approaches to develop new diagnostic methods, optimise drug-efficacy monitoring protocols, 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 diagnostic.
b) Utilise specific estimates of parasite egg, antigen and DNA clearance post treatment to evaluate 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) 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 conducted seven field programmes in Mayuge District, Uganda. These 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 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 have lower infection levels post observed treatments. Most adults enrolled in our study had never been treated before. MDA progammes need to reach these adults to reduce long term illness and reduce the chance of them reinfecting the children, who still show susceptibility to infection.

Infection data are being used in mathematical models to help us understand why these Ugandan communities are not clearing as expected with repeated treatments. Models highlight the limitations of 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 drug.

We have published 10 papers and presented findings at several international conferences, including the British Society for Parasitology, American Society for Tropical Medicine and Hygiene, Evolution, and 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, expert meetings of the Bill and Melinda Gates Foundation, FIND diagnostics, Global Schistosomiasis Alliance and Coalition for Neglected Tropical Diseases Meetings.

In March 2018, we and 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 transmission cycle of schistosomiasis, the role of unsafe defecation and water contact behaviours. The benefits of this small scale intervention were seen and a larger programme is needed to raise awareness, engage the community and help spread understanding about the disease and how to control. Such a project could increase the uptake in medicine to treat the infection as well as help empower the community of issues such as sanitation and safe water.

Other dissemination activities include teaching courses in prisons, working with primary school aged children at local events and networks, running public engagement stalls at music festivals, giving talks at schools and in pubs.
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