A research agenda for malaria eradication: drugs

Antimalarial drugs will be essential tools at all stages of malaria elimination along the path towards eradication, including the early control or "attack" phase to drive down transmission and the later stages of maintaining interruption of transmission, preventing reintroduction of malaria, and eliminating the last residual foci of infection. Drugs will continue to be used to treat acute malaria illness and prevent complications in vulnerable groups, but better drugs are needed for elimination-specific indications such as mass treatment, curing asymptomatic infections, curing relapsing liver stages, and preventing transmission. The ideal malaria eradication drug is a coformulated drug combination suitable for mass administration that can be administered in a single encounter at infrequent intervals and that results in radical cure of all life cycle stages of all five malaria species infecting humans. Short of this optimal goal, highly desirable drugs might have limitations such as targeting only one or two parasite species, the priorities being Plasmodium falciparum and Plasmodium vivax. The malaria research agenda for eradication should include research aimed at developing such drugs and research to develop situation-specific strategies for using both current and future drugs to interrupt malaria transmission.     

A research agenda for malaria eradication: vaccines

Vaccines could be a crucial component of efforts to eradicate malaria. Current attempts to develop malaria vaccines are primarily focused on Plasmodium falciparum and are directed towards reducing morbidity and mortality. Continued support for these efforts is essential, but if malaria vaccines are to be used as part of a repertoire of tools for elimination or eradication of malaria, they will need to have an impact on malaria transmission. We introduce the concept of "vaccines that interrupt malaria transmission" (VIMT), which includes not only "classical" transmission-blocking vaccines that target the sexual and mosquito stages but also pre-erythrocytic and asexual stage vaccines that have an effect on transmission. VIMT may also include vaccines that target the vector to disrupt parasite development in the mosquito. Importantly, if eradication is to be achieved, malaria vaccine development efforts will need to target other malaria parasite species, especially Plasmodium vivax, where novel therapeutic vaccines against hypnozoites or preventive vaccines with effect against multiple stages could have enormous impact. A target product profile (TPP) for VIMT is proposed and a research agenda to address current knowledge gaps and develop tools necessary for design and development of VIMT is presented.     

A research agenda for malaria eradication: modeling

Malaria modeling can inform policy and guide research for malaria elimination and eradication from local implementation to global policy. A research and development agenda for malaria modeling is proposed, to support operations and to enhance the broader eradication research agenda. Models are envisioned as an integral part of research, planning, and evaluation, and modelers should ideally be integrated into multidisciplinary teams to update the models iteratively, communicate their appropriate use, and serve the needs of other research scientists, public health specialists, and government officials. A competitive and collaborative framework will result in policy recommendations from multiple, independently derived models and model systems that share harmonized databases. As planned, modeling results will be produced in five priority areas: (1) strategic planning to determine where and when resources should be optimally allocated to achieve eradication; (2) management plans to minimize the evolution of drug and pesticide resistance; (3) impact assessments of new and needed tools to interrupt transmission; (4) technical feasibility assessments to determine appropriate combinations of tools, an associated set of target intervention coverage levels, and the expected timelines for achieving a set of goals in different socio-ecological settings and different health systems; and (5) operational feasibility assessments to weigh the economic costs, capital investments, and human resource capacities required.     

A research agenda for malaria eradication: vector control

Different challenges are presented by the variety of malaria transmission environments present in the world today. In each setting, improved control for reduction of morbidity is a necessary first step towards the long-range goal of malaria eradication and a priority for regions where the disease burden is high. For many geographic areas where transmission rates are low to moderate, sustained and well-managed application of currently available tools may be sufficient to achieve local elimination. The research needs for these areas will be to sustain and perhaps improve the effectiveness of currently available tools. For other low-to-moderate transmission regions, notably areas where the vectors exhibit behaviours such as outdoor feeding and resting that are not well targeted by current strategies, new interventions that target predictable features of the biology/ecologies of the local vectors will be required. To achieve elimination in areas where high levels of transmission are sustained by very efficient vector species, radically new interventions that significantly reduce the vectorial capacity of wild populations will be needed. Ideally, such interventions should be implemented with a one-time application with a long-lasting impact, such as genetic modification of the vectorial capacity of the wild vector population.     

A research agenda for malaria eradication: diagnoses and diagnostics

Many of malaria's signs and symptoms are indistinguishable from those of other febrile diseases. Detection of the presence of Plasmodium parasites is essential, therefore, to guide case management. Improved diagnostic tools are required to enable targeted treatment of infected individuals. In addition, field-ready diagnostic tools for mass screening and surveillance that can detect asymptomatic infections of very low parasite densities are needed to monitor transmission reduction and ensure elimination. Antibody-based tests for infection and novel methods based on biomarkers need further development and validation, as do methods for the detection and treatment of Plasmodium vivax. Current rapid diagnostic tests targeting P. vivax are generally less effective than those targeting Plasmodium falciparum. Moreover, because current drugs for radical cure may cause serious side effects in patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency, more information is needed on the distribution of G6PD-deficiency variants as well as tests to identify at-risk individuals. Finally, in an environment of very low or absent malaria transmission, sustaining interest in elimination and maintaining resources will become increasingly important. Thus, research is required into the context in which malaria diagnostic tests are used, into diagnostics for other febrile diseases, and into the integration of these tests into health systems.     

A research agenda to underpin malaria eradication

The interruption of malaria transmission worldwide is one of the greatest challenges for international health and development communities. The current expert view suggests that, by aggressively scaling up control with currently available tools and strategies, much greater gains could be achieved against malaria, including elimination from a number of countries and regions; however, even with maximal effort we will fall short of global eradication. The Malaria Eradication Research Agenda (malERA) complements the current research agenda--primarily directed towards reducing morbidity and mortality--with one that aims to identify key knowledge gaps and define the strategies and tools that will result in reducing the basic reproduction rate to less than 1, with the ultimate aim of eradication of the parasite from the human population. Sustained commitment from local communities, civil society, policy leaders, and the scientific community, together with a massive effort to build a strong base of researchers from the endemic areas will be critical factors in the success of this new agenda.     

A research agenda for malaria eradication: health systems and operational research

Health systems research and development is needed to support the global malaria eradication agenda. In this paper, we (the malERA Consultative Group on Health Systems and Operational Research) focus on the health systems needs of the elimination phase of malaria eradication and consider groupings of countries at different stages along the pathway to elimination. We examine the difference between the last attempt at eradication of malaria and more recent initiatives, and consider the changing health system challenges as countries make progress towards elimination. We review recent technological and theoretical developments related to health systems and the renewed commitment to strengthening health systems for universal access and greater equity. Finally, we identify a number of needs for research and development, including tools for analyzing and improving effective coverage and strengthening decision making and discuss the relevance of these needs at all levels of the health system from the community to the international level.     

A research agenda for malaria eradication: basic science and enabling technologies

Today's malaria control efforts are limited by our incomplete understanding of the biology of Plasmodium and of the complex relationships between human populations and the multiple species of mosquito and parasite. Research priorities include the development of in vitro culture systems for the complete life cycle of P. falciparum and P. vivax and the development of an appropriate liver culture system to study hepatic stages. In addition, genetic technologies for the manipulation of Plasmodium need to be improved, the entire parasite metabolome needs to be characterized to identify new druggable targets, and improved information systems for monitoring the changes in epidemiology, pathology, and host-parasite-vector interactions as a result of intensified control need to be established to bridge the gap between bench, preclinical, clinical, and population-based sciences.     

A research agenda for malaria eradication: monitoring, evaluation, and surveillance

Monitoring, evaluation, and surveillance measure how well public health programs operate over time and achieve their goals. As countries approach malaria elimination, these activities will need to shift from measuring reductions in morbidity and mortality, to detecting infections (with or without symptoms) and measuring transmission. Thus, the monitoring and evaluation and surveillance research and development agenda needs to develop the tools and strategies that will replace passive surveillance of morbidity with active and prompt detection of infection, including confirmation of interruption of transmission by detecting present and past infections, particularly in mobile populations. The capacity to assess trends and respond without delay will need to be developed, so that surveillance itself becomes an intervention. Research is also needed to develop sensitive field tests that can detect low levels of parasitaemia, together with strategies for their implementation. Other areas to explore include the rigorous evaluation of the utility of more detailed maps of disease and infection incidence and prevalence, the development of new maps to inform programmatic responses and the use of surveillance technologies based on cell phone or real-time internet Web-based reporting. Because any new strategies for monitoring and evaluation and surveillance for eradication have major implications for program implementation, research is also needed to test systems of delivery for acceptability, feasibility, efficiency, cost-effectiveness, and community engagement. Finally, there is a clear need to systematically review the information from past elimination efforts for malaria and other infectious diseases.     

Aging bone and cartilage: cross-cutting issues

Aging is a major risk factor for osteoarthritis and osteoporosis. Yet, these are not necessary outcomes of aging, and the relationship between age-related changes in bone and cartilage and development of disease is not clear. There are some well-described cellular changes associated with aging in multiple tissues that appear to be fundamental to the decline in function of cartilage and bone. A better understanding of age-related changes in cells and tissues is necessary to mitigate or, hopefully, avoid loss of bone and cartilage with aging. In addition, a better understanding of the dynamics of tissue maintenance in vivo is critical to developing tissue replacement and repair therapies. The role of stem cells in this process, and why tissues are not well maintained with advancing age, are frontiers for future aging research.     

The role of research in viral disease eradication and elimination programs: lessons for malaria eradication

By examining the role research has played in eradication or regional elimination initiatives for three viral diseases--smallpox, poliomyelitis, and measles--we derive nine cross-cutting lessons applicable to malaria eradication. In these initiatives, some types of research commenced as the programs began and proceeded in parallel. Basic laboratory, clinical, and field research all contributed notably to progress made in the viral programs. For each program, vaccine was the lynchpin intervention, but as the programs progressed, research was required to improve vaccine formulations, delivery methods, and immunization schedules. Surveillance was fundamental to all three programs, whilst polio eradication also required improved diagnostic methods to identify asymptomatic infections. Molecular characterization of pathogen isolates strengthened surveillance and allowed insights into the geographic source of infections and their spread. Anthropologic, sociologic, and behavioural research were needed to address cultural and religious beliefs to expand community acceptance. The last phases of elimination and eradication became increasingly difficult, as a nil incidence was approached. Any eradication initiative for malaria must incorporate flexible research agendas that can adapt to changing epidemiologic contingencies and allow planning for posteradication scenarios.     

A schistosomiasis research agenda

There is a long and rich history of research and control in the field of schistosomiasis that has resulted in major scientific and public health accomplishments. Examples of such findings and accomplishments include immunologic regulation in chronic infections, the association of helminth infections with Th1-regulating Th2-type immune responses, the critical role of interleukin-13 in fibrogenesis, and the development and validation of the "dose pole" for determining praziquantel dosages in the field. Perhaps in part because of this broad and successful history, those who work on schistosomiasis come from a wide variety of backgrounds and interests. While such variety is enriching to the field, it sometimes results in diverse opinions about which of the many research opportunities should be pursued. Such diversity, we believe, has at times led to a divisiveness that has harmed overall progress in the field. Partly in response to such events, we have worked with as many of those interested in schistosomiasis as we could identify to develop what we feel is a comprehensive and cohesive agenda for schistosomiasis research.     

Prospects for malaria eradication in sub-Saharan Africa

Background

A characteristic of Plasmodium falciparum infections is the gradual acquisition of clinical immunity resulting from repeated exposures to the parasite. While the molecular basis of protection against clinical malaria remains unresolved, its effects on epidemiological patterns are well recognized. Accumulating epidemiological data constitute a valuable resource that must be intensively explored and interpreted as to effectively inform control planning.

Methodology/Principal Finding

Here we apply a mathematical model to clinical data from eight endemic regions in sub-Saharan Africa. The model provides a quantitative framework within which differences in age distribution of clinical disease are assessed in terms of the parameters underlying transmission. The shorter infectious periods estimated for clinical infections induce a regime of bistability of endemic and malaria-free states in regions of mesoendemic transmission. The two epidemiological states are separated by a threshold that provides a convenient measure for intervention design. Scenarios of eradication and resurgence are simulated.

Conclusions/Significance

In regions that support mesoendemic transmission, intervention success depends critically on reducing prevalence below a threshold which separates endemic and malaria-free regimes.     

A collaboratively-derived science-policy research agenda

The need for policy makers to understand science and for scientists to understand policy processes is widely recognised. However, the science-policy relationship is sometimes difficult and occasionally dysfunctional; it is also increasingly visible, because it must deal with contentious issues, or itself becomes a matter of public controversy, or both. We suggest that identifying key unanswered questions on the relationship between science and policy will catalyse and focus research in this field. To identify these questions, a collaborative procedure was employed with 52 participants selected to cover a wide range of experience in both science and policy, including people from government, non-governmental organisations, academia and industry. These participants consulted with colleagues and submitted 239 questions. An initial round of voting was followed by a workshop in which 40 of the most important questions were identified by further discussion and voting. The resulting list includes questions about the effectiveness of science-based decision-making structures; the nature and legitimacy of expertise; the consequences of changes such as increasing transparency; choices among different sources of evidence; the implications of new means of characterising and representing uncertainties; and ways in which policy and political processes affect what counts as authoritative evidence. We expect this exercise to identify important theoretical questions and to help improve the mutual understanding and effectiveness of those working at the interface of science and policy.     

A research agenda for helminth diseases of humans: intervention for control and elimination

Recognising the burden helminth infections impose on human populations, and particularly the poor, major intervention programmes have been launched to control onchocerciasis, lymphatic filariasis, soil-transmitted helminthiases, schistosomiasis, and cysticercosis. The Disease Reference Group on Helminth Infections (DRG4), established in 2009 by the Special Programme for Research and Training in Tropical Diseases (TDR), was given the mandate to review helminthiases research and identify research priorities and gaps. A summary of current helminth control initiatives is presented and available tools are described. Most of these programmes are highly dependent on mass drug administration (MDA) of anthelmintic drugs (donated or available at low cost) and require annual or biannual treatment of large numbers of at-risk populations, over prolonged periods of time. The continuation of prolonged MDA with a limited number of anthelmintics greatly increases the probability that drug resistance will develop, which would raise serious problems for continuation of control and the achievement of elimination. Most initiatives have focussed on a single type of helminth infection, but recognition of co-endemicity and polyparasitism is leading to more integration of control. An understanding of the implications of control integration for implementation, treatment coverage, combination of pharmaceuticals, and monitoring is needed. To achieve the goals of morbidity reduction or elimination of infection, novel tools need to be developed, including more efficacious drugs, vaccines, and/or antivectorial agents, new diagnostics for infection and assessment of drug efficacy, and markers for possible anthelmintic resistance. In addition, there is a need for the development of new formulations of some existing anthelmintics (e.g., paediatric formulations). To achieve ultimate elimination of helminth parasites, treatments for the above mentioned helminthiases, and for taeniasis and food-borne trematodiases, will need to be integrated with monitoring, education, sanitation, access to health services, and where appropriate, vector control or reduction of the parasite reservoir in alternative hosts. Based on an analysis of current knowledge gaps and identification of priorities, a research and development agenda for intervention tools considered necessary for control and elimination of human helminthiases is presented, and the challenges to be confronted are discussed.     

A research agenda for helminth diseases of humans: modelling for control and elimination

Mathematical modelling of helminth infections has the potential to inform policy and guide research for the control and elimination of human helminthiases. However, this potential, unlike in other parasitic and infectious diseases, has yet to be realised. To place contemporary efforts in a historical context, a summary of the development of mathematical models for helminthiases is presented. These efforts are discussed according to the role that models can play in furthering our understanding of parasite population biology and transmission dynamics, and the effect on such dynamics of control interventions, as well as in enabling estimation of directly unobservable parameters, exploration of transmission breakpoints, and investigation of evolutionary outcomes of control. The Disease Reference Group on Helminth Infections (DRG4), established in 2009 by the Special Programme for Research and Training in Tropical Diseases (TDR), was given the mandate to review helminthiases research and identify research priorities and gaps. A research and development agenda for helminthiasis modelling is proposed based on identified gaps that need to be addressed for models to become useful decision tools that can support research and control operations effectively. This agenda includes the use of models to estimate the impact of large-scale interventions on infection incidence; the design of sampling protocols for the monitoring and evaluation of integrated control programmes; the modelling of co-infections; the investigation of the dynamical relationship between infection and morbidity indicators; the improvement of analytical methods for the quantification of anthelmintic efficacy and resistance; the determination of programme endpoints; the linking of dynamical helminth models with helminth geostatistical mapping; and the investigation of the impact of climate change on human helminthiases. It is concluded that modelling should be embedded in helminth research, and in the planning, evaluation, and surveillance of interventions from the outset. Modellers should be essential members of interdisciplinary teams, propitiating a continuous dialogue with end users and stakeholders to reflect public health needs in the terrain, discuss the scope and limitations of models, and update biological assumptions and model outputs regularly. It is highlighted that to reach these goals, a collaborative framework must be developed for the collation, annotation, and sharing of databases from large-scale anthelmintic control programmes, and that helminth modellers should join efforts to tackle key questions in helminth epidemiology and control through the sharing of such databases, and by using diverse, yet complementary, modelling approaches.     

WHO research agenda for radiofrequency fields

The World Health Organization (WHO) has recently published a new research agenda for radiofrequency fields. The document lists high priority and other research needs for health effects research, subdivided into epidemiology, human studies, animal studies, cellular studies and mechanisms, and for social science research.