Marcel Tanner

Schistosomiasis and water resources development: systematic review, meta-analysis, and estimates of people at risk

An estimated 779 million people are at risk of schistosomiasis, of whom 106 million (13.6%) live in irrigation schemes or in close proximity to large dam reservoirs. We identified 58 studies that examined the relation between water resources development projects and schistosomiasis, primarily in African settings. We present a systematic literature review and meta-analysis with the following objectives: (1) to update at-risk populations of schistosomiasis and number of people infected in endemic countries, and (2) to quantify the risk of water resources development and management on schistosomiasis. Using 35 datasets from 24 African studies, our meta-analysis showed pooled random risk ratios of 2.4 and 2.6 for urinary and intestinal schistosomiasis, respectively, among people living adjacent to dam reservoirs. The risk ratio estimate for studies evaluating the effect of irrigation on urinary schistosomiasis was in the range 0.02-7.3 (summary estimate 1.1) and that on intestinal schistosomiasis in the range 0.49-23.0 (summary estimate 4.7). Geographic stratification showed important spatial differences, idiosyncratic to the type of water resources development. We conclude that the development and management of water resources is an important risk factor for schistosomiasis, and hence strategies to mitigate negative effects should become integral parts in the planning, implementation, and operation of future water projects.

A Research Agenda to Underpin Malaria Eradication

Pedro Alonso and colleagues introduce the Malaria Eradication Research Agenda (malERA) initiative and the set of articles published in this PLoS Medicine Supplement that distill the research questions key to malaria eradication.

Randomised placebo-controlled trial of iron supplementation and malaria chemoprophylaxis for prevention of severe anaemia and malaria in Tanzanian infants

BACKGROUND Malaria and anaemia, especially that due to iron deficiency, are two leading causes of morbidity worldwide. Little is known about the relative contribution of Plasmodium falciparum infection and iron deficiency to the aetiology of anaemia in malaria-endemic areas. We undertook a randomised comparison of different strategies for control of anaemia and malaria in infants, including an assessment of the effect of iron supplementation on malaria susceptibility. METHODS 832 infants born at one hospital in a malaria-hyperendemic area of Tanzania between January and October, 1995, were randomly assigned to group DI, receiving daily oral iron (2 mg/kg daily) plus weekly Deltaprim (3.125 mg pyrimethamine plus 25 mg dapsone); group IP, receiving iron plus weekly placebo; group DP, receiving daily placebo plus weekly Deltaprim; or group PP. supplementation was given from 8 to 24 weeks of age, and the weekly chemoprophylaxis from 8 to 48 weeks. The frequency of severe anaemia (packed-cell volume < 25%) and malaria episodes was assessed through a combination of passive case detection and cross-sectional surveys. FINDINGS The groups that received iron supplementation had a lower frequency of severe anaemia than those that did not receive iron (0.62 vs 0.87 cases per person-year; protective efficacy 28.8% [95% CI 6.3-45.8). Iron supplementation had no effect on the frequency of malaria (0.87 vs 1.00 cases per person-year; protective efficacy 12.8% [-12.8 to 32.5]). The groups that received malaria prophylaxis had lower frequencies of both severe anaemia (0.45 vs 1.04 episodes per person-year; protective efficacy 57.3% [43.0-67.9]) and malaria (0.53 vs 1.34 episodes per person-year; protective efficacy 60.5% [48.2-69.9]) than the groups that did not receive prophylaxis. After the end of the intervention period, children who had received malaria chemoprophylaxis had higher rates of severe anaemia and malaria than non-chemoprophylaxis groups (relative risks 2.2 [1.3-3.7] and 1.8 [1.3-2.6]). INTERPRETATION Malaria chemoprophylaxis during the first year of life was effective in prevention of malaria and anaemia but apparently impaired the development of natural immunity. Iron supplementation was effective in preventing severe anaemia without increasing susceptibility to malaria. Our findings support iron supplementation of infants to prevent iron-deficiency anaemia, even in malaria-endemic areas.

Intermittent treatment for malaria and anaemia control at time of routine vaccinations in Tanzanian infants: a randomised, placebo-controlled trial

BACKGROUND Clinical malaria and severe anaemia are major causes of paediatric hospital admission and death in many malaria-endemic settings. In the absence of an effective and affordable vaccine, control programmes continue to rely on case management while attempting the large-scale deployment of insecticide-treated nets. We did a randomised, placebo-controlled trial to assess the efficacy and safety of intermittent sulphadoxine-pyrimethamine treatment on the rate of malaria and severe anaemia in infants in a rural area of Tanzania. METHODS We randomly assigned 701 children living in Ifakara, southern Tanzania, sulphadoxine-pyrimethamine or placebo at 2, 3, and 9 months of age. All children received iron supplementation between 2 and 6 months of age. The intervention was given alongside routine vaccinations delivered through WHOs Expanded Program on Immunisation (EPI). The primary outcome measures were first or only episode of clinical malaria, and severe anaemia in the period from recruitment to 1 year of age. Morbidity monitoring through a hospital-based passive case-detection system was complemented by cross-sectional surveys at 12 and 18 months of age. Results were expressed in terms of protective efficacy (100 [1-hazard ratio]%) and analysis was by intention to treat. FINDINGS 40 children dropped out (16 died, 11 migrated, 12 parents withdrew consent, and one for other reasons). Intermittent sulphadoxine-pyrimethamine treatment was well tolerated and no drug-attributable adverse events were recorded. During the first year of life, the rate of clinical malaria (events per person-year at risk) was 0.15 in the sulphadoxine-pyrimethamine group versus 0.36 in the placebo group (protective efficacy 59% [95% CI 41-72]), and the rate of severe anaemia was 0.06 in the sulphadoxine-pyrimethamine group versus 0.11 in the placebo group (50% [8-73]). Serological responses to EPI vaccines were not affected by the intervention. INTERPRETATION This new approach to malaria control reduced the rate of clinical malaria and severe anaemia by delivering an available and affordable drug through the existing EPI system. Data are urgently needed to assess the potential cost-effectiveness of intermittent treatment in areas with different patterns of malaria endemicity.

Effect of large-scale social marketing of insecticide-treated nets on child survival in rural Tanzania.

BACKGROUND Insecticide-treated nets have proven efficacy as a malaria-control tool in Africa. However, the transition from efficacy to effectiveness cannot be taken for granted. We assessed coverage and the effect on child survival of a large-scale social marketing programme for insecticide-treated nets in two rural districts of southern Tanzania with high perennial malaria transmission. METHODS Socially marketed insecticide-treated nets were introduced step-wise over a 2-year period from May, 1997, in a population of 480000 people. Cross-sectional coverage surveys were done at baseline and after 1, 2, and 3 years. A demographic surveillance system (DSS) was set up in an area of 60000 people to record population, births, and deaths. Within the DSS area, the effect of insecticide-treated nets on child survival was assessed by a case-control approach. Cases were deaths in children aged between 1 month and 4 years. Four controls for each case were chosen from the DSS database. Use of insecticide-treated nets and potential confounding factors were assessed by questionnaire. Individual effectiveness estimates from the case-control study were combined with coverage to estimate community effectiveness. FINDINGS Insecticide-treated net coverage of infants in the DSS area rose from less than 10% at baseline to more than 50% 3 years later. Insecticide-treated nets were associated with a 27% increase in survival in children aged 1 month to 4 years (95% CI 3-45). Coverage in such children was higher in areas with longer access to the programme. The modest average coverage achieved by 1999 in the two districts (18% in children younger than 5 years) suggests that insecticide-treated nets prevented 1 in 20 child deaths at that time. INTERPRETATION Social marketing of insecticide-treated nets has great potential for effective malaria control in rural African settings.

From 'one medicine' to 'one health' and systemic approaches to health and well-being

Faced with complex patterns of global change, the inextricable interconnection of humans, pet animals, livestock and wildlife and their social and ecological environment is evident and requires integrated approaches to human and animal health and their respective social and environmental contexts. The history of integrative thinking of human and animal health is briefly reviewed from early historical times, to the foundation of universities in Europe, up to the beginning of comparative medicine at the end of the 19th century. In the 20th century, Calvin Schwabe coined the concept of “one medicine”. It recognises that there is no difference of paradigm between human and veterinary medicine and both disciplines can contribute to the development of each other. Considering a broader approach to health and well-being of societies, the original concept of “one medicine” was extended to “one health” through practical implementations and careful validations in different settings. Given the global health thinking in recent decades, ecosystem approaches to health have emerged. Based on complex ecological thinking that goes beyond humans and animals, these approaches consider inextricable linkages between ecosystems and health, known as “ecosystem health”. Despite these integrative conceptual and methodological developments, large portions of human and animal health thinking and actions still remain in separate disciplinary silos. Evidence for added value of a coherent application of “one health” compared to separated sectorial thinking is, however, now growing. Integrative thinking is increasingly being considered in academic curricula, clinical practice, ministries of health and livestock/agriculture and international organizations. Challenges remain, focusing around key questions such as how does “one health” evolve and what are the elements of a modern theory of health? The close interdependence of humans and animals in their social and ecological context relates to the concept of “human-environmental systems”, also called “social-ecological systems”. The theory and practice of understanding and managing human activities in the context of social-ecological systems has been well-developed by members of The Resilience Alliance and was used extensively in the Millennium Ecosystem Assessment, including its work on human well-being outcomes. This in turn entails systems theory applied to human and animal health. Examples of successful systems approaches to public health show unexpected results. Analogous to “systems biology” which focuses mostly on the interplay of proteins and molecules at a sub-cellular level, a systemic approach to health in social-ecological systems (HSES) is an inter- and trans-disciplinary study of complex interactions in all health-related fields. HSES moves beyond “one health” and “eco-health”, expecting to identify emerging properties and determinants of health that may arise from a systemic view ranging across scales from molecules to the ecological and socio-cultural context, as well from the comparison with different disease endemicities and health systems structures.

Operational strategies to achieve and maintain malaria elimination

Summary Present elimination strategies are based on recommendations derived during the Global Malaria Eradication Program of the 1960s. However, many countries considering elimination nowadays have high intrinsic transmission potential and, without the support of a regional campaign, have to deal with the constant threat of imported cases of the disease, emphasising the need to revisit the strategies on which contemporary elimination programmes are based. To eliminate malaria, programmes need to concentrate on identification and elimination of foci of infections through both passive and active methods of case detection. This approach needs appropriate treatment of both clinical cases and asymptomatic infections, combined with targeted vector control. Draining of infectious pools entirely will not be sufficient since they could be replenished by imported malaria. Elimination will thus additionally need identification and treatment of incoming infections before they lead to transmission, or, more realistically, embarking on regional initiatives to dry up importation at its source.

A research agenda for malaria eradication: drugs.

The Malaria Eradication Research Agenda (malERA) Consultative Group on Drugs present a research and development agenda to ensure that appropriate drugs are available for use in malaria eradication.

Resistance to antifolates in Plasmodium falciparum monitored by sequence analysis of dihydropteroate synthetase and dihydrofolate reductase alleles in a large number of field samples of diverse origins

Resistance of Plasmodium falciparum to antifolate chemotherapy is a significant problem where combinations such as Fansidar (pyrimethamine-sulfadoxine; PYR-SDX) are used in the treatment of chloroquine-resistant malaria. Antifolate resistance has been associated with variant sequences of dihydrofolate reductase (DHFR) and dihydropteroate synthetase (DHPS), the targets of PYR and SDX respectively. However, while the nature and distribution of mutations in the dhfr gene are well established, this is not yet the case for dhps. We have thus examined by DNA sequence analysis 141 field samples from several geographical regions with differing Fansidar usage (West and East Africa, the Middle East and Viet Nam) to establish a database of the frequency and repertoire of dhps mutations, which were found in 60% of the samples. We have also simultaneously determined from all samples their dhfr sequences, to better understand the relationship of both types of mutation to Fansidar resistance. Whilst the distribution of mutations was quite different across the regions surveyed, it broadly mirrored our understanding of relative Fansidar usage. In samples taken from individual patients before and after drug treatment, we found an association between the more highly mutated forms of dhps and/or dhfr and parasites that were not cleared by antifolate therapy. We also report a novel mutation in a Pakistani sample at position 16 of DHFR (A16S) that is combined with the familiar C59R mutation, but is wild-type at position 108. This is the first observation in a field sample of a mutant dhfr allele where the 108 codon is unchanged.

Safety and Immunogenicity of RTS,S/AS02D Malaria Vaccine in Infants

BACKGROUND The RTS,S/AS malaria vaccine is being developed for delivery through the World Health Organizations Expanded Program on Immunization (EPI). We assessed the feasibility of integrating RTS,S/AS02D into a standard EPI schedule for infants. METHODS In this phase 2B, single-center, double-blind, controlled trial involving 340 infants in Bagamoyo, Tanzania, we randomly assigned 340 infants to receive three doses of either the RTS,S/AS02D vaccine or the hepatitis B vaccine at 8, 12, and 16 weeks of age. All infants also received a vaccine containing diphtheria and tetanus toxoids, whole-cell pertussis vaccine, and conjugated Haemophilus influenzae type b vaccine (DTPw/Hib). The primary objectives were the occurrence of serious adverse events during a 9-month surveillance period and a demonstration of noninferiority of the responses to the EPI vaccines (DTPw/Hib and hepatitis B surface antigen) with coadministration of the RTS,S/AS02D vaccine, as compared with the hepatitis B vaccine. The detection of antibodies against Plasmodium falciparum circumsporozoite and efficacy against malaria infection were secondary objectives. RESULTS At least one serious adverse event was reported in 31 of 170 infants who received the RTS,S/AS02D vaccine (18.2%; 95% confidence interval [CI], 12.7 to 24.9) and in 42 of 170 infants who received the hepatitis B vaccine (24.7%; 95% CI, 18.4 to 31.9). The results showed the noninferiority of the RTS,S/AS02D vaccine in terms of antibody responses to EPI antigens. One month after vaccination, 98.6% of infants receiving the RTS,S/AS02D vaccine had seropositive titers for anticircumsporozoite antibodies on enzyme-linked immunosorbent assay (ELISA). During the 6-month period after the third dose of vaccine, the efficacy of the RTS,S/AS02D vaccine against first infection with P. falciparum malaria was 65.2% (95% CI, 20.7 to 84.7; P=0.01). CONCLUSIONS The use of the RTS,S/AS02D vaccine in infants had a promising safety profile, did not interfere with the immunologic responses to coadministered EPI antigens, and reduced the incidence of malaria infection. (ClinicalTrials.gov number, NCT00289185.)