Epidemiology and evolution of zoonotic schistosomiasis in a changing world

Lead Research Organisation: Royal Veterinary College
Department Name: Pathology and Pathogen Biology

Abstract

Schistosomiasis, caused by schistosome parasitic worms is a disease of profound medical and veterinary importance, inflicting unnecessary suffering on poor rural communities in many parts of the developing world, with the greatest burden within sub-Saharan Africa. Environmental change, through natural phenomena or human interventions, such as dam constructions or drug treatments, can substantially impact upon the dynamics and distribution of this disease, with potential positive and negative effects upon human and animal health. Such activities, combined with changes in agricultural practices, place selective pressures on human and animal schistosomes and increase the opportunities for mixing of different species. This mixing within the human or animal hosts can result in novel hybrids which may influence their potential for disease transmission and morbidity. Focusing within Niger and Senegal, our multidisciplinary proposal aims to understand the populations at risk of infection and disease with novel zoonotic hybrid schistosomes. The results obtained regarding the potential role of animal schistosomiasis in maintained infection hot spots, should prove valuable for control programmes, including recent plans for schistosomiasis elimination. We will also enhance the capacity of our West African partner institutions, from schistosome and host identification, population genetic analyses, together with partnership with industry to produce and evaluate new rapid mapping diagnostic tools for the field.

Technical Summary

Schistosomiasis is a disease caused by different species of parasitic worms, called schistosomes. It is a Neglected Tropical Disease (NTD) of profound medical and veterinary importance, inflicting unnecessary suffering on poor rural communities in many parts of the developing world, with the greatest burden within sub-Saharan Africa (SSA). Recent changes in selective pressures following, for instance, new dam constructions/irrigation systems and/or altered agricultural practices, combined with increased mass drug administration programmes, may all impact the availability of suitable definitive and intermediate hosts for schistosomes, and hence potential for both intra- and inter-specific interactions within such hosts. Furthermore, when humans and their livestock come into closer water contact, novel zoonotic hybrid schistosome species may evolve and establish as a consequence, with subsequent changes in parasite life history traits, transmission potential, morbidity profiles and intervention success. Empirical studies of such potential evolutionary changes under natural conditions are lacking. The research proposed here will contribute to the major push to control and eliminate schistosomiasis as a public health problem as recently put forward in the WHO NTD roadmap. It is essential to discover fully the extent of schistosome zoonotic infections as this may well influence progress in reducing transmission in many regions of West Africa in addition to Niger and Senegal. We hope to learn lessons that will inform and guide future control activities and assist local livestock farmers. Very little attention has been paid to the impact of animal schistosomiasis on domestic ruminants in SSA and in the vast majority of rural settings little is done in the way of treatment. Our findings will play a significant role in helping to control this debilitating disease that is so commonly associated with impoverished rural populations.

Planned Impact

Schistosomiasis is a NTD of profound medical and veterinary importance, inflicting unnecessary suffering on poor rural communities in many parts of the developing world, with the greatest burden within SSA. Our research will contribute to the major push to control and eliminate schistosomiasis as a public health problem as recently put forward in the WHO NTD roadmap. It is essential to discover fully the extent of schistosome zoonotic infections as this may well influence progress in reducing transmission in many regions of West Africa in addition to Niger and Senegal.

The proposed research will also provide development, optimization and application of SOPs for novel diagnostics, future mapping and genetic analyses of zoonotic hybrid schistosomes in SSA and in doing so will enhance the capacity of the staff of our African partner institutions in aspects of disease research, surveillance and control. There are many man-made environmental changes planned and in progress in Senegal and Niger associated with water development which will impact on schistosomiasis, these changes will alter the distribution of human and animal populations and will lead to changes in the distribution of the snail intermediate hosts essential for transmission. By capacity building and training we hope to increase expertise within local research teams so that they are better able to monitor and assess the impact of these environmental changes.

The results produced here will be fed directly back into international and national policy, including WHO guidelines and national control progamme implementation. This will be directly achievable here through our Niger coapplicant AG, and our Senegalese Research Partner IT, directing the national control programmes within county, assisted by SCI and hence the PI JPW and the Research Partner AF.

Our pilot data from one area in Niger has indicated an apparent 'hot-spot' transmission area in Niger - where very high prevalence (82% 2006-96.4% 2009) and intensities of apparent urogenital schistosomiasis were maintained despite high coverage annual/bi-annual MDA. Our molecular analyses revealed that 87% of these children were in fact infected with a novel zoonotic hybrid infection. If the current studies reveal further hotspots of maintained transmission are due to zoonotic infections this has implications for control. If our PZQ efficacy assays reveal continued high efficacy of PZQ in terms of ERR, but high reinfection rates, we can propose more regular PZQ treatments/MDA in such areas to impact the juvenile maturing worms (which are not responsive to PZQ). If our PZQ efficacy assays reveals, in contrast, a reduced efficacy in hybrid versus single infections we can propose higher PZQ doses, from 40 mg/kg to 60 mg/kg and emphasize further the need for PZQ alternatives. If the outputs from our research so indicate, pressure will be placed for the implementation of concurrent methods for schistosomiasis control in livestock, including potential bovine vaccine development and/or PZQ chemotherapy, akin to that currently employed for zoonotic S. japonicum transmission in China. This will thereby assure impact and benefit to those people, and their livestock, in Niger and Senegal in both the short and the long term.

A full appreciation of the interactions taking place between schistosomes of humans and animals and associated morbidities will ultimately lead to improved animal management practices with a concurrent improvement in animal health which will in turn assist in lifting rural human populations out of poverty.

Furthermore, in addition to the applied significance of this work, which translates directly into control, we hope the research findings will also be of fundamental value to the academic community as we believe that we are witnessing the evolution of a zoonotic infection.

Publications

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Antonovics J (2017) The evolution of transmission mode. in Philosophical transactions of the Royal Society of London. Series B, Biological sciences

 
Description In pursuit of "a world free of schistosomiasis", the WHO recently set ambitious goals for the 'elimination as a public health problem of schistosomiasis within selected SSA countries by 2025'. The approach to achieve this vision, targeted Mass Drug Administration (MDA) to school-aged children, assumes that schistosomiasis in SSA is a human-only disease. The role of animal schistosomiasis in SSA, either in terms of disease control, economic impact, or zoonotic risk for maintaining transmission to humans, has been largely ignored.
Our research identified numerous ongoing 'hot-spots' of extremely high urogenital schistosomiasis prevalence, intensity and transmission, within children and adults, across Niger and Senegal, despite long-term, high-coverage MDA. Molecular analyses revealed that the infecting parasites were not human S. haematobium as assumed. Instead, 80-100% were novel viable hybridized schistosomes, resulting from successful crosses between human and livestock schistosome species. Hybridized livestock:livestock schistosome species infecting children were also identified, providing evidence of hybrid vigour and increased host-range.
Elucidating transmission dynamics of viable hybridizing multi-host parasites is of fundamental importance. Likewise, understanding the extent and dynamics of transmission is essential if the impact of control to potential elimination of zoonotic schistosome infections is to be realised. An extensive, systematic programme of sampling from humans (children and adult faeces and urine), livestock (cattle, sheep and goats; live-sampling and abattoir surveys), together with wildlife and snail intermediate-hosts surveys, has been performed across transmission sites under contrasting high or low levels of recent anthropogenic change within Senegal and Niger.
We ensured extensive local capacity-building and north-south and south-south training, as well as the development, optimization and application of traditional and novel methodologies for improved parasitological, clinical and molecular diagnostics. Morbidity and economic analyses from humans and livestock, combined with systematic review of the limited available animal data, highlighted current gaps.
Ethonographic studies and focus group meetings, across broad tiers of society, evaluated awareness of animal schistosomiasis and routes of transmission, the priorities and motivators of stakeholders and identified barriers against, and avenues to promote, impact.
Novel mathematical models, encompassing hybridization amongst multi-host parasites, illustrated the role of livestock schistosome species in perpetuating ongoing transmission amongst humans. Further predictive models, incorporating our empirical data, are in progress.
All parasite material has been bio-banked for future open-access research. To date, this study has generated 12 primary publications and provided evidence for the key role of livestock schistosomes which is being directly fed into policy, including WHO guidelines and national control programmes. The PI's direct role on WHO expert advisory boards for drug efficacy, NTD elimination and disease control monitoring and evaluation panels facilitates this knowledge transfer.
Thus, this research contributes to sustainable disease control and development strategies for the poorest humans and their livestock in the developing world.
Exploitation Route Our primary objective was a better understanding of the evolution, ecology and transmission dynamics of the emerging disease threat from zoonotic schistosomiasis in Africa, to the health of humans and their livestock. More generally, we aimed to use the research findings as a model of the role of evolution of host ranges and inter-specific parasite hybridization within major taxonomic groups, in a period of rapid, anthropocentric environmental change.
Key outcomes to date include: i) modified attitudes and practice of those at threat from schistosomiasis; ii) improved local capacity and expertise to diagnose and monitor disease in humans and animals; iii) improved access to human and veterinary-formula drugs; iv) elucidation of the socio-economic impact and costs of animal schistosomiasis to subsistence farmers; v) elucidation of transmission dynamics and evolution of novel hybridizing parasite combinations. The ultimate aim is to inform effective international policy on control of zoonotic schistosomiasis.
We have observed direct educational benefits to staff and students across Senegal and Niger, upskilling and equipping them to diagnose human and livestock schistosomiasis. We revealed a need for portable point-of contact ultrasonography morbidity diagnosis within Senegal, and, through South-South and North-South collaboration, developed this expertise and capacity within local communities most in need.
Working with WHO, Merck-KGA and SCI, we maximised access to human-formula praziquantel. Our research revealed a completely unmet demand for veterinary-formula praziquantel, which was leading to inappropriate use of human-formula praziquantel in livestock. By negotiation, working with Bayer pharma, Ministries of Health, Senegalese Veterinary Services, together with WHO, we obtained permission to import veterinary praziquantel into West Africa, to undertake a proof-of-principle application and efficacy study. Such access helps ensure the sustained efficacy of the only available drug for human and animal schistosomes.
Detailed appreciation of interactions between schistosomes of humans and animals will provide decision-makers and national and community health services with improved tools to target interventions. Pressure will be now placed for the implementation of modified praziquantel treatment regimens for people and animals living in zoonotic high transmission zones, applying a One Health framework for schistosomiasis control.
We are collaborating closely with the Schistosomiasis National Control Programs in Senegal and Niger. Results to date have been discussed at WHO Expert Advisory Group meetings on evaluating drug efficacy by the PI, JPW, who heads the Praziquantel drug efficacy WHO working group and the co-I, Dr Amadou Garba, who now holds a WHO NTD department senior post. JPW has also been elected to the new 'WHO Guideline Development Group (GDG) for the implementation of control and elimination of schistosomiasis'. Thus, both PI and co-I are in ideal positions to advise and influence the translation of this novel research into international guidelines and practice.
In response, we have already seen the role of zoonotic hybrid schistosomes and implications for control included within key WHO publications and draft 'elimination target guidelines'. JPW has also presented the need for a One Health approach to achieve schistosomiasis control targets to UK funders, donors and within the Houses of Parliament, both Commons and Lords.
Sectors Agriculture, Food and Drink,Communities and Social Services/Policy,Creative Economy,Education,Environment,Healthcare,Leisure Activities, including Sports, Recreation and Tourism,Government, Democracy and Justice,Culture, Heritage, Museums and Collections,Pharmaceuticals and Medical Biotechnology,Other

URL http://www.londonntd.org/news/all-party-parliamentary-group-on-malaria-and-ntds-%C2%A0translating-ntd-research-into-policy
 
Description E.g. 1 Challenge and Impact Solution: Within-country capacity to diagnose and treat human schistosomiasis. Provision of diagnostic equipment and competency training in basic parasitological techniques: 5 technicians, 2 PhD Students, 10 MSc/BSc students (plus 5 UK PhD, 3 MSc, 3 BSc students); Provision of advanced 3-month training in molecular diagnostics and analyses for 2 Senegalese PhD students in the UK (RVC). Provision of South-South and North-South Advanced Training and Capacity in Clinical diagnosis: Ultrasonography is the diagnostic tool of choice for detecting pathologic conditions associated with schistosomiasis, both in hospital and field-based settings. It is non-invasive and well accepted by communities. Whilst our Niger team, led through Dr Amadou Garba, ensured excellent ultrasonography facilities and expertise, there was no comparable expertise nor facilities available within Senegal. We therefore arranged for a young Senegalese doctor, Dr Chiekh Binetou-Fall, to travel to Niger and partner with our Niger co-I for one month of intensive competency training. We then purchased and imported a portable ultrasound for the Senegalese team. Dr Binetou-Fall is now fully proficient in schistosomiasis-related ultrasonography to assess early and late stage morbidity profiles as part of our ZELS programme and his clinical activities in general. He has also transferred his skills to further colleagues and complementary research/clinical programmes across Senegal. Added-value was through significantly increased community compliance for treatment within certain schools previously refusing treatment, following one-to-one meetings with village leaders and teachers showing bladder morbidity profiles of infected children and the subsequent recrudescence post-treatment. E.g.2 - Challenge and Impact Solution: within-country capacity to diagnose and treat livestock schistosomiasis. As above, personnel and equipment were provided for capacity in both basic and advanced diagnosis of animal schistosomiases. In addition, a key finding from the ethnographic research was that local farmers and veterinarians in high prevalence areas knew animal schistosomiasis was a major problem and were treating their animals with a mixture of ineffective drugs. Notably, individuals were observed to be purchasing, through markets and/or veterinarians, donated human-formula (Merck KGA) praziquantel. The only currently available veterinary-formula praziquantel within West Africa is 'Tenicure' - at tapeworm dosage and combined with Levamisole. Usage of this product at labelled dosage is ineffective against schistosomes, thereby exacerbating the risk of emerging drug resistance, and due to its combination dose of Levamisole, the volume could not be increased without toxic Levamisole dosage. Owners reported access to appropriate drugs and dosage information was their most significant limiting factor for successful control. Our challenge to this unforeseen need and practice was to promote access and appropriate use of veterinary-approved praziquantel (and alleviating current misuse of human-formula praziquantel). This required extensive dialogue and collaboration with pharma, in particular Bayer, the Senegalese Veterinary Services, the Ministry of Health and customs, to license, import and appropriate supply and evaluate efficacy (and local demand) of a schistosome-specific formula and dosage. This is underway and the longer-term impact of this should be improved access to treatment and subsequent health of livestock, reduced risk of drug resistance, increased awareness and compliance of MDA in humans.
First Year Of Impact 2016
Sector Agriculture, Food and Drink,Communities and Social Services/Policy,Education,Environment,Healthcare,Government, Democracy and Justice,Culture, Heritage, Museums and Collections,Pharmaceuticals and Medical Biotechnology
Impact Types Cultural,Societal,Economic,Policy & public services

 
Description Global Challenges Research Fund Impact Accelerator Award (GCRF-IAA)
Amount £40,000 (GBP)
Funding ID BB/GCRF-IAA/17/19 
Organisation Biotechnology and Biological Sciences Research Council (BBSRC) 
Sector Public
Country United Kingdom
Start 12/2017 
End 03/2018
 
Description Global Challenges Research Fund-International Accelerator Award (GCRF-IAA)
Amount £49,000 (GBP)
Organisation Biotechnology and Biological Sciences Research Council (BBSRC) 
Sector Public
Country United Kingdom
Start 12/2016 
End 03/2017
 
Description Blog report on field trip and open day activities 
Form Of Engagement Activity A magazine, newsletter or online publication
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Public/other audiences
Results and Impact Redaction of an article for the BioMed Central Bug Bitten Blog
This article have been shared 71 times on Facebook but it doesn't mean anything on the number of persons


Linked with 2 public outreach events at the NHM - One for the NTD day and the other for the European Researchers Night.
Year(s) Of Engagement Activity 2015
URL http://blogs.biomedcentral.com/bugbitten/2015/12/18/researching-emerging-zoonotic-schistosomiasis-in...
 
Description Educational workshop for livestock owners and families held in the rural village communities of our main ZELS grant (also part of IAA grant). 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Study participants or study members
Results and Impact The workshops were conducted following the focus group and interview study to ascertain knowledge, attitudes and practices of villagers, health workers and local decision makers to symptoms associated with schistosomiasis. The workshops educational material were tailored to these findings.

Some provisional results of the focus groups:-
• Locals has good awareness of the syndrome and the usage of medications in animals.
• Perception of the impact of the disease in animals was higher than anticipated.
• Knowledge of the zoonotic nature of the disease was variable.
• Locals has limited awareness of the usage of Praziquantel medications of the dissemination and purpose in children.
• Resources were often a concern when deciding on ability to seek medical attention.

Workshop attendants - e.g. Barkedji
Villages represented n = 9; Number of attendees n = 26.
Attendees included both Men and Women from the villages as well as local teachers and veterinary workers.

Feedback from the Workshop
Local feedback was extremely positive, education surrounding the treatment in children was particularly well received. Women in particular felt the education was of great value to them and positive feedback relating to change in health seeking behaviour and access to medications was received from all female participants and a representative from each village. Requests to continue the research and provide more assistance in both children and animals were also received.
Year(s) Of Engagement Activity 2016,2017
 
Description Guest Lecture 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Other audiences
Results and Impact Webster, J.P. (2016). Multiple-hosts and Multiple-parasites - cross species transmission and implication for One Health Disease Control. Invited Keynote/Plenary lecture. British Ecological Society Annual Retreat. (18th January)
Year(s) Of Engagement Activity 2016
 
Description International Guest Lecture - Molecular Helminthology conference 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Other audiences
Results and Impact Webster, J.P. (2017). Selective pressures and drug efficacy in a changing world. Invited Guest Lecture. Molecular Helminthology, Cape Cod, USA. (22nd March).
Year(s) Of Engagement Activity 2017
 
Description International Guest Lecture - Webster, J.P. (2017). Epidemiology and Evolution of zoonotic schistosomes in a changing world. Invited Annual Carmody Guest Lecture. Carlton University, Ottowa, Canada. (17th March). 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Postgraduate students
Results and Impact Webster, J.P. (2017). Epidemiology and Evolution of zoonotic schistosomes in a changing world. Invited Annual Carmody Guest Lecture. Carleton University, Ottowa, Canada. (17th March).
Year(s) Of Engagement Activity 2017
 
Description Invited Expert Advisor presentation/working group leader. World Health Organisation (WHO) headquarters 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Policymakers/politicians
Results and Impact Webster, J.P. (2018). Monitoring praziquantel efficacy. Invited Expert Advisor presentation/working group leader. World Health Organisation (WHO) headquarters, Geneva, Switzerland (26th-28th February).
Year(s) Of Engagement Activity 2018
 
Description Invited Guest Keynote Lecture The Royal Society, London, UK, 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Other audiences
Results and Impact Webster, J.P. (2017). A One Health approach to controlling zoonotic schistosomiasis in a changing world. (Roy's Symposium). Invited Guest Keynote Lecture The Royal Society, London, UK,
Year(s) Of Engagement Activity 2017
 
Description Invited Guest Keynote Lecture. British Society for Parasitology Autumn Symposium, Linnaen Society, London, 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Other audiences
Results and Impact Webster, J.P. (2017). Zoonotic schistosomiasis in a changing world. Invited Guest Keynote Lecture. British Society for Parasitology Autumn Symposium, Linnaen Society, London, UK (28th Sept.).
Year(s) Of Engagement Activity 2017
 
Description Invited Guest Lecture. British Society for Parasitology Spring Symposium, 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Other audiences
Results and Impact Invited Key Note Lecture to general scientific audience.Webster, J.P. (2018). Epidemiology an Evolution of Zoonotic schistosomiasis in Afruca: challenges for reaching the WHO elimination targets. Invited Guest Lecture. British Society for Parasitology Spring Symposium, Aberystwyth University, UK
Year(s) Of Engagement Activity 2018
 
Description Invited Guest Speaker. All Members Working Group Malaria and NTDs. House of Commons, Houses of Parliament, Westminster, UK. 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Policymakers/politicians
Results and Impact Webster, J.P. (2017). A One Health approach to controlling neglected tropical diseases: successes and challenges. Invited Guest Speaker. All Members Working Group Malaria and NTDs. House of Commons, Houses of Parliament, Westminster, UK. (12th December.).
Year(s) Of Engagement Activity 2017
 
Description Journalist field visit to Senegalese sites and magazine article on our research 
Form Of Engagement Activity A magazine, newsletter or online publication
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Public/other audiences
Results and Impact A science journalist from Germany accompanied us on one of our Senegalese field trips and interviewed us about the ZELS programme in general - his first written magazine article is published, entitled:

Der Killerwurm (in German); Suddeutsche Zeitung Nr. 280, Samstag/Sonntag, ¾. (December 2016).

He is currently also writing an article for Science on the same topic.
Year(s) Of Engagement Activity 2016
 
Description Public and online interview: 'Zoonotic parasites, and underappreciated Area' for the Infectious Disease Hub 
Form Of Engagement Activity A press release, press conference or response to a media enquiry/interview
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Media (as a channel to the public)
Results and Impact 'Zoonotic parasites, and underappreciated Area' for the Infectious Disease Hub (September 2018) http://www.londonntd.org/news/zoonotic-parasites-an-underappreciated-area-%E2%80%93-an-interview-with-joanne-webster
Year(s) Of Engagement Activity 2017
URL http://www.londonntd.org/news/zoonotic-parasites-an-underappreciated-area-%E2%80%93-an-interview-wit...