A Research and Development Agenda for the Control and Elimination of Human Helminthiases

In this issue of PLoS Neglected Tropical Diseases, the Disease Reference Group on Helminth Infections (DRG4) has put forward a collection of eight reviews that, taken together, outline a compelling research and development agenda for the control and elimination of helminth diseases of humans (http://www.ploscollections.org/helminths [1]–[8]). Emphasis is placed on six major helminth infections: (i) soil-transmitted helminthiasis; (ii) schistosomiasis; (iii) lymphatic filariasis; (iv) onchocerciasis; (v) food-borne trematodiasis; and (vi) cysticercosis/taeniasis. Selection of these helminthiases is justified on multiple grounds. Firstly, as shown in Table 1, more than half of the world's population is at risk of one or several of these helminthiases, and hundreds of millions of people are currently infected. Secondly, consequences of the mainly long-term chronic infection include suffering, stigmatisation, subtle and gross morbidity (e.g., anaemia, limb deformations and blindness), and premature death, hence causing an intolerable global burden [9]–[17]. These features, in turn, exacerbate poverty [18]–[20]. Thirdly, there is growing commitment at all levels—from local communities to politicians, philanthropic organisations, and civil society—to control and eventually eliminate/eradicate the major human helminthiases. 
 
 
 
Table 1 
 
Helminth Infections Emphasised by DRG4 for Development of a Research Agenda for Control and Elimination. 
 
 
 
Figure 1 shows that the six helminthiases are at distinctively different stages of control and elimination with geographical idiosyncrasies for some of them [21]. Several helminthiases have been targeted for elimination (e.g., lymphatic filariasis and onchocerciasis in the Americas), and progress made thus far gives hope that this goal can indeed be achieved by 2015 or 2020 if certain conditions are met [14], [21]. For schistosomiasis and soil-transmitted helminthiasis, discussions are escalating to shift the focus from control to elimination [22], [23], and in Africa, the African Programme for Onchocerciasis Control (APOC) is also moving towards this goal [24]. The pivotal role of research, coupled with teaching and training of strong cadres of researchers from endemic settings as essential backbones and platforms to design, implement, and adapt the control and elimination agenda for major helminthiases as well as other tropical diseases, cannot be emphasised enough [25]–[27]. 
 
 
 
Figure 1 
 
Stages of control/elimination of the six helminthiases emphasised by DRG4. 
 
 
 
In 2007/2008, the Special Programme for Research and Training in Tropical Diseases (TDR), based at and executed by the World Health Organization (WHO), and co-sponsored by the United Nations Children's Fund (UNICEF), the United Nations Development Programme (UNDP), the World Bank and WHO, initiated a network of disease-specific and thematic reference groups (DRGs/TRGs). DRG4 was particularly prolific, as witnessed in the collection of authoritative reviews presented here. This accompanying editorial summarises the goal, objectives and expected outcomes of the DRGs/TRGs global research “think tank”. Next, light is shed on the composition of DRG4, its mode of operation and its first outputs. It is then argued that PLoS Neglected Tropical Diseases is an appropriate outlet for the studies reviewed and synthesised by DRG4. Indeed, open access to the identified and ranked research priorities by all stakeholders is a major asset and is likely to reinforce the control and elimination agenda of the major helminthiases.

In this issue of PLoS Neglected Tropical Diseases, the Disease Reference Group on Helminth Infections (DRG4) has put forward a collection of eight reviews that, taken together, outline a compelling research and development agenda for the control and elimination of helminth diseases of humans (http://www.ploscollections. org/helminths; [1][2][3][4][5][6][7][8]). Emphasis is placed on six major helminth infections: (i) soiltransmitted helminthiasis; (ii) schistosomiasis; (iii) lymphatic filariasis; (iv) onchocerciasis; (v) food-borne trematodiasis; and (vi) cysticercosis/taeniasis. Selection of these helminthiases is justified on multiple grounds. Firstly, as shown in Table 1, more than half of the world's population is at risk of one or several of these helminthiases, and hundreds of millions of people are currently infected. Secondly, consequences of the mainly long-term chronic infection include suffering, stigmatisation, subtle and gross morbidity (e.g., anaemia, limb deformations and blindness), and premature death, hence causing an intolerable global burden [9][10][11][12][13][14][15][16][17]. These features, in turn, exacerbate poverty [18][19][20]. Thirdly, there is growing commitment at all levels-from local communities to politicians, philanthropic organisations, and civil society-to control and eventually eliminate/eradicate the major human helminthiases. Figure 1 shows that the six helminthiases are at distinctively different stages of control and elimination with geographical idiosyncrasies for some of them [21]. Several helminthiases have been targeted for elimination (e.g., lymphatic filariasis and onchocerciasis in the Americas), and progress made thus far gives hope that this goal can indeed be achieved by 2015 or 2020 if certain conditions are met [14,21]. For schistosomiasis and soil-transmitted helminthiasis, discussions are escalating to shift the focus from control to elimination [22,23], and in Africa, the African Programme for Onchocerciasis Control (APOC) is also moving towards this goal [24]. The pivotal role of research, coupled with teaching and training of strong cadres of researchers from endemic settings as essential backbones and platforms to design, implement, and adapt the control and elimination agenda for major helminthiases as well as other tropical diseases, cannot be emphasised enough [25][26][27].
In 2007/2008, the Special Programme for Research and Training in Tropical Diseases (TDR), based at and executed by the World Health Organization (WHO), and co-sponsored by the United Nations Children's Fund (UNICEF), the United Nations Development Programme (UNDP), the World Bank and WHO, initiated a network of disease-specific and thematic reference groups (DRGs/TRGs). DRG4 was particularly prolific, as witnessed in the collection of authoritative reviews presented here. This accompanying editorial summarises the goal, objectives and expected outcomes of the DRGs/TRGs global research ''think tank''. Next, light is shed on the composition of DRG4, its mode of operation and its first outputs. It is then argued that PLoS Neglected Tropical Diseases is an appropriate outlet for the studies reviewed and synthesised by DRG4. Indeed, open access to the identified and ranked research priorities by all stakeholders is a major asset and is likely to reinforce the control and elimination agenda of the major helminthiases.

A Global Research ''Think Tank''
The idea to create a global network of DRGs and TRGs as a major international research ''think tank'' stems from the fourth external review of TDR that took place between February 2005 and May 2006 [28]. The role and operation of this ''think tank'' were incorporated into the 10-year strategic plan of TDR, which is endorsed by WHO. A key recommendation of the aforementioned external review was that TDR should shift its emphasis from pursuing a model of disease portfolio (''neglected diseases'') [29] to infectious diseases of poverty-related research needs (''needy populations''). As a result of this thinking, the 10-year strategy and underlying business plan of TDR recommended two strong pillars to position and further enhance the organisation's strategic advantages in a rapidly changing global landscape of funding, research and development: (i) knowledge management that should lead to the concept of stewardship, and (ii) capacity building that should foster empowerment [30].
Conceptualised in 2007/2008, a total of 10 reference groups, six of them with a disease-specific focus, and the remaining four with a thematic and cross-cutting emphasis, were initiated [2] (Table 2; see also Table S1 in [2]). Each reference group comprises 10-14 international experts. Groups are chaired and co-chaired by renowned scientists, at least one of whom is based in a developing country. A competitively selected young career research fellow is offered the opportunity to be part of the group, primarily pursuing research within the realm of the group, but also charged with some limited operational and managerial tasks to ascertain smooth operation of the groups. The reference groups are hosted by WHO country offices in Africa, Asia, and Latin America.
As per TDR's latest 10-year strategy and vision, the global network of DRGs and TRGs operate within the guiding principles of knowledge management and capacity building, thus emphasising stewardship and empowerment. The specific objectives are to systematically review, debate, and synthesise available information and to define and rate research priorities. This is facilitated by regular meetings (it was initially planned that the groups would meet once a year for 3-5 days), usually in the hosting country of a specific group. Broad stakeholder consultation, usually at the outset of the meetings, was adopted as an integral part of the modus operandi of the groups.   At the outset, the group identified research gaps and pursued a multi-criteria assessment, including stakeholder consultation, and Delphi approach that ultimately resulted in a consolidated list of the 10 top research priorities. This forms the ''white paper'' of the DRG4, i.e., recognising and pursuing these priorities in order to achieve control and elimination of major human helminthiases. This ''white paper'' is co-authored by the entire group [2]. Next, an in-depth analysis outlines the problem of human helminthiases, emphasising the omnipresence of single and multiple species parasitic worm infections and their intricate relationship with poverty [1]. Visualising this collection as house, the reviews highlighting the problem of human helminthiases, and issues towards control and elimination, are like the foundation upon which the building is erected (Figure 2). Key proposed responses for the helminthiases control and elimination agenda are reviewed in four separate pieces that are the main building blocks of the house. These include basic research and enabling technologies [3], new and improved intervention tools and strategies, such as drugs, vaccines, and for some of the helminthiases also vector control [6], diagnostics [4], and mathematical modelling to inform policy and reinforce research [5]. Understanding socialecological contexts, environmental determinants, and health systems forms the first layer of the roof [7]. Health research and capacity building in developing country settings is of such pivotal importance that it is layered on top of a well-built house, and hence reinforces the agenda [8].
It is, perhaps, interesting to note that key research and development (R&D) issues have already been discussed in connection with a malaria eradication research agenda (malERA). Facilitated by a 2-year broadly integrative and iterative process led by a core team, and assisted by various experts groups and involving more than 250 scientists, programme managers and decision-makers from the public and private sectors in a series of consultations, the malERA went live in a special issue of PLoS Medicine in early 2011 [27]. Similar R&D issues were identified in parallel by the malERA and the series presenting the research agenda for helminth infections of humans. Once the collection of malERA papers came out, they served as an inspiration to also publish the comprehensive R&D agenda pertaining to human helminthiases in a collection of reviews, and PLoS Neglected Tropical Diseases was deemed a suitable outlet. Both agendas feature basic science and enabling technologies [3,31], diagnoses and diagnostics [4,32], modelling [5,33], and health systems issues [7,34]. While the helminthiases agenda has a single chapter on interventions (due to the fact that, for instance, interventions such as anti-helminth vaccines are in earlier stages of development for use in humans [35]), in the malERA, there are three separate contributions for interventions: drugs, vaccines, and vector control [36][37][38]. This difference further emphasises the neglect in R&D funding for novel and repositioned intervention tools to control human helminth infections as opposed to malaria [39]. Additionally, the malERA views the issues of monitoring, evaluation, and surveillance (the latter further developed as ''surveillance as an intervention'') of such great importance that space is given for a full contribution [40]. Together with a piece on crosscutting issues for eradication, lessons learned from the first malaria eradication era in the 1950s and 1960s, and the aforementioned umbrella [27], the mal-ERA certainly is a key resource for developing control and elimination/eradication agendas for human infectious diseases, including human helminthiases. However, the research agenda for helminthiases is unique in its contribution of a separate article fully considering the issues of capacity building for health research and disease control in endemic countries Figure 2. A research agenda for the control and elimination of major helminthiasis put forth by DRG4. This figure synthesises the key written outputs from DRG4, visualising this collection of eight reviews as a house (strong foundation, major building blocks and a two-layered roof). doi:10.1371/journal.pntd.0001646.g002 www.plosntds.org [8], which is absent in the malERA collection. Both collections therefore should be considered together as prime examples of major outputs produced by think tanks, driven by core writing teams and stakeholder engagement in the current global efforts to help control and eliminate poverty-related diseases [21].

Going Live in PLoS Neglected Tropical Diseases
In terms of writing, the various DRGs and TRGs were charged to produce annual reports. Additionally, the groups were requested to have these reports further developed into stand-alone comprehensive Technical Report Series, to be published by the WHO. Unfortunately, at the time these reports were submitted to TDR, the organisation sailed through troubled waters, delaying internal processing and external peer review. Yet, there is new traction and it is hoped that the planned WHO Technical Report Series will soon come to bear. In the meantime, the Disease Reference Group on Zoonoses and Marginalized Infectious Diseases (DRG6) disseminated a most useful overview article through the open-access journal Parasites & Vectors [41].
The efforts made by DRG4 to produce no less than eight major reviews are commended and PLoS Neglected Tropical Diseases clearly is an appropriate outlet for this collection of articles. To wit, within 2-  [42,43]. Indeed, all of the six helminthiases emphasised by DRG4 were part of the initial scope of PLoS Neglected Tropical Diseases. Meanwhile, the scope of the journal has broadened considerably [44], and now also includes a growing number of bacterial, protozoal, viral, and ectoparasitic infections, but helminthiases still figure prominently. Indeed, as shown in Table 3, more than 20% of the over 1,300 original articles, reviews, and front-matter pieces focus on helminth infections.

Lessons Learned and Next Steps
Sixty-five years after the landmark publication of Norman R. Stool entitled ''This Wormy World'' [45], it is clear that helminthiases are still widespread and continue to pose a huge public health problem. Indeed, a situation analysis reveals that more than half of the word's population is at risk of helminth infection, more than a billion people are currently infected, often with multiple species, and helminthiases are rife where poverty and malnutrition prevail, in the face of lack of access to basic infrastructure (e.g., clean water and sanitation) and hygiene [17,20,46]. These facts form the foundation of the current article collection [1,2]. Responses on how to control and eventually eliminate human helminthiases require ethically, technically and scientifically sound research to improve current tools and strategies, as summarised in the present helminthiasis agenda [2][3][4][5][6]. Research and capacity building must accompany the entire process and innovation is key to developing and validating the next generation of tools and strategies [8]. For example, there is a need for developing rapid and inexpensive integrated mapping approaches for those helminthiases where the extent of the problem is not yet appreciated [47]. The recent development of high-resolution, spatially explicit global databases for helminthiases and other neglected tropical diseases provides an exciting new opportunity for targeting control interventions, and subsequent monitoring, evaluation, and surveillance [48,49]. Importantly, once the emphasis shifts from morbidity control towards transmission control and finally local elimination, the need for highly accurate diagnostics tools must be stressed. Indeed, the diagnostics must be adapted to the current stage of a control programme [50]. Moreover, lessons learned from past successful helminthiases control and elimination programmes emphasise the need for integrated approaches with close collaboration between different sectors (e.g., health, education, and water) and long-term political commitment [51][52][53].
These issues must be seen in rapidly changing demographic, health systems, and social-ecological contexts [7]. A deep understanding at different spatial and temporal scales is mandatory so that some of the most ancient afflictions of humankind can be consigned to history in the not too distant future.