Detection of asymptomatic malaria in Asian countries: a meta-analysis of diagnostic accuracy.

BACKGROUND: Achieving malaria elimination requires the targeting of the human reservoir of infection, including those patients with asymptomatic infection. The objective was to synthesise evidence on the accuracy of the rapid-onsite diagnostic tests (RDTs) and microscopy for the detection of asymptomatic malaria as part of the surveillance activities in Asian countries. METHODS: This was a meta-analysis of diagnostic test accuracy. Relevant studies that evaluated the diagnostic performance of RDTs and microscopy for detection of asymptomatic malaria were searched in health-related electronic databases. The methodological quality of the studies included was assessed using the QUADAS-2 tool. RESULTS: Ten studies assessing RDT and/or microscopy were identified. The diagnostic accuracies in all these studies were verified by PCR. Overall, the pooled sensitivities of RDT, as well as microscopy for detection of any malaria parasites in asymptomatic participants, were low, while their pooled specificities were almost ideal. For the detection of Plasmodium falciparum, pooled sensitivity by RDT (59%, 95%CI:16-91%) or microscopy (55%, 95%CI: 25-82%) were almost comparable. For detection of Plasmodium vivax, pooled sensitivity of RDT (51%, 95% CI:7-94%) had also the comparable accuracy of microscopy (54%, 95%CI,11-92%). Of note are the wide range of sensitivity and specificity. CONCLUSION: The findings of this meta-analysis suggest that RDTs and microscopy have limited sensitivity and are inappropriate for the detection of asymptomatic Plasmodium infections. Other methods including a combination of PCR-based strategies, Loop-Mediated Isothermal Amplification (LAMP) technique must be considered to target these infections, in order to achieve malaria elimination. However, more data is needed for the wide acceptance and feasibility of these approaches. Studies to explore the role of asymptomatic and sub-patent infections in the transmission of malaria are of critical importance and are recommended.

Participatory approaches for raising awareness among subsistence farmers in Tanzania about the spread of insecticide resistance in malaria vectors and the possible link to improper agricultural pesticide use.

BACKGROUND: Insecticide resistance is a key barrier to long-term malaria control, and it may be exacerbated by poor agricultural pesticide use. Current practices, however, do not link public health and agricultural pesticide use. This study investigated the perspectives of farmers and other stakeholders regarding the integration of agricultural and public health measures to address resistance. Additionally, the feasibility of participatory workshops to increase the farmers' understanding and participation in pesticide stewardship was assessed. METHODS: Four themes were investigated: pesticide awareness, practices, and opinions of; insecticide resistance in malaria vectors; the effectiveness of current malaria prevention tools; and the links between agricultural and public health pesticide usage. Participatory workshops and field training were held with entomologists, farmers, and agricultural specialists, focusing on agro-ecosystem practices related to pest control; and local farmers were involved in live-testing for insecticides resistance of local Anopheles mosquitoes. RESULTS: Most farmers (94%) considered pesticides effective, and nearly half of them (n = 198, 46.4%) could identify and name crop pests and diseases, mostly using local names. Three quarters were unaware of mosquito larvae in their fields, and only 7% considered their fields as potential sources of mosquitoes. Two thirds were uninformed of any effects that agricultural pesticides may have on mosquitoes, and three quarters had never heard of resistance in malaria mosquitoes. Experts from various sectors acknowledged that agricultural pesticides might impact malaria control through increasing resistance. They did, however, emphasize the importance of crop protection and advocated for the use of pesticides sparingly and non-chemical approaches. Farmers learnt how to discriminate between malaria vectors and non-vectors, identify agricultural pests and diseases, choose and use pesticides effectively, and conduct resistance tests during the participatory workshops. CONCLUSION: This study emphasizes the significance of enhancing subsistence farmers' awareness of mosquito ecology as well as merging public health and agricultural pest management measures. Participatory techniques have the potential to raise stakeholder awareness and engagement, resulting in more effective resistance management.

Analysis of nucleic acids extracted from rapid diagnostic tests reveals a significant proportion of false positive test results associated with recent malaria treatment.

BACKGROUND: Surveillance programmes often use malaria rapid diagnostic tests (RDTs) to determine the proportion of the population carrying parasites in their peripheral blood to assess the malaria transmission intensity. Despite an increasing number of reports on false-negative and false-positive RDT results, there is a lack of systematic quality control activities for RDTs deployed in malaria surveillance programmes. METHODS: The diagnostic performance of field-deployed RDTs used for malaria surveys was assessed by retrospective molecular analysis of the blood retained on the tests. RESULTS: Of the 2865 RDTs that were collected in 2018 on Bioko Island and analysed in this study, 4.7% had a false-negative result. These false-negative RDTs were associated with low parasite density infections. In 16.6% of analysed samples, masked pfhrp2 and pfhrp3 gene deletions were identified, in which at least one Plasmodium falciparum strain carried a gene deletion. Among all positive RDTs analysed, 28.4% were tested negative by qPCR and therefore considered to be false-positive. Analysing the questionnaire data collected from the participants, this high proportion of false-positive RDTs could be explained by P. falciparum histidine rich protein 2 (PfHRP2) antigen persistence after recent malaria treatment. CONCLUSION: Malaria surveillance depending solely on RDTs needs well-integrated quality control procedures to assess the extent and impact of reduced sensitivity and specificity of RDTs on malaria control programmes.

Diagnostic performance and comparison of ultrasensitive and conventional rapid diagnostic test, thick blood smear and quantitative PCR for detection of low-density Plasmodium falciparum infections during a controlled human malaria infection study in Equatorial Guinea.

BACKGROUND: Progress towards malaria elimination has stagnated, partly because infections persisting at low parasite densities comprise a large reservoir contributing to ongoing malaria transmission and are difficult to detect. This study compared the performance of an ultrasensitive rapid diagnostic test (uRDT) designed to detect low density infections to a conventional RDT (cRDT), expert microscopy using Giemsa-stained thick blood smears (TBS), and quantitative polymerase chain reaction (qPCR) during a controlled human malaria infection (CHMI) study conducted in malaria exposed adults (NCT03590340). METHODS: Blood samples were collected from healthy Equatoguineans aged 18-35 years beginning on day 8 after CHMI with 3.2 × 103 cryopreserved, infectious Plasmodium falciparum sporozoites (PfSPZ Challenge, strain NF54) administered by direct venous inoculation. qPCR (18s ribosomal DNA), uRDT (Alere™ Malaria Ag P.f.), cRDT [Carestart Malaria Pf/PAN (PfHRP2/pLDH)], and TBS were performed daily until the volunteer became TBS positive and treatment was administered. qPCR was the reference for the presence of Plasmodium falciparum parasites. RESULTS: 279 samples were collected from 24 participants; 123 were positive by qPCR. TBS detected 24/123 (19.5% sensitivity [95% CI 13.1-27.8%]), uRDT 21/123 (17.1% sensitivity [95% CI 11.1-25.1%]), cRDT 10/123 (8.1% sensitivity [95% CI 4.2-14.8%]); all were 100% specific and did not detect any positive samples not detected by qPCR. TBS and uRDT were more sensitive than cRDT (TBS vs. cRDT p = 0.015; uRDT vs. cRDT p = 0.053), detecting parasitaemias as low as 3.7 parasites/µL (p/µL) (TBS and uRDT) compared to 5.6 p/µL (cRDT) based on TBS density measurements. TBS, uRDT and cRDT did not detect any of the 70/123 samples positive by qPCR below 5.86 p/µL, the qPCR density corresponding to 3.7 p/µL by TBS. The median prepatent periods in days (ranges) were 14.5 (10-20), 18.0 (15-28), 18.0 (15-20) and 18.0 (16-24) for qPCR, TBS, uRDT and cRDT, respectively; qPCR detected parasitaemia significantly earlier (3.5 days) than the other tests. CONCLUSIONS: TBS and uRDT had similar sensitivities, both were more sensitive than cRDT, and neither matched qPCR for detecting low density parasitaemia. uRDT could be considered an alternative to TBS in selected applications, such as CHMI or field diagnosis, where qualitative, dichotomous results for malaria infection might be sufficient.

Activation of TCR Vδ1+ and Vδ1-Vδ2- γδ T Cells upon Controlled Infection with Plasmodium falciparum in Tanzanian Volunteers.

Our understanding of the human immune response to malaria remains incomplete. Clinical trials using whole-sporozoite-based vaccination approaches such as the Sanaria PfSPZ Vaccine, followed by controlled human malaria infection (CHMI) to assess vaccine efficacy offer a unique opportunity to study the immune response during Plasmodium falciparum infection. Diverse populations of T cells that are not restricted to classical HLA (unconventional T cells) participate in the host response during Plasmodium infection. Although several populations of unconventional T cells exist, the majority of studies focused on TCR Vγ9Vδ2 cells, the most abundant TCR γδ cell population in peripheral blood. In this study, we dissected the response of three TCR γδ cell subsets and mucosal-associated invariant T cells in healthy volunteers immunized with PfSPZ Vaccine and challenged by CHMI using Sanaria PfSPZ Challenge. Using a flow cytometry-based unbiased analysis followed by T cell cloning, several findings were made. Whereas major ex vivo alterations were not detectable after immunization with PfSPZ Vaccine, TCR Vδ2, and mucosal-associated invariant T cells expanded after asexual blood-stage parasitemia induced by CHMI. CHMI, but not vaccination, also induced the activation of TCR Vδ1 and Vδ1-Vδ2- γδ T cells. The activated TCR Vδ1 cells were oligoclonal, suggesting clonal expansion, and upon repeated CHMI, showed diminished response, indicating long-term alterations induced by blood-stage parasitemia. Some TCR Vδ1 clones recognized target cells in the absence of parasite-derived Ags, thus suggesting recognition of self-molecules. These findings reveal the articulate participation of different populations of unconventional T cells to P. falciparum infection.

Testing the contextual Interaction theory in a UHC pilot district in South Africa.

BACKGROUND: World-wide, there is growing universal health coverage (UHC) enthusiasm. The South African government began piloting policies aimed at achieving UHC in 2012. These UHC policies have been and are being rolled out in the ten selected pilot districts. Our study explored policy implementation experiences of 71 actors involved in UHC policy implementation, in one South African pilot district using the Contextual Interaction Theory (CIT) lens. METHOD: Our study applied a two-actor deductive theory of implementation, Contextual Interaction Theory (CIT) to analyse 71 key informant interviews from one National Health Insurance (NHI) pilot district in South Africa. The theory uses motivation, information, power, resources and the interaction of these to explain implementation experiences and outcomes. The research question centred on the utility of CIT tenets in explaining the observed implementation experiences of actors and outcomes particularly policy- practice gaps. RESULTS: All CIT central tenets (information, motivation, power, resources and interactions) were alluded to by actors in their policy implementation experiences, a lack or presence of these tenets were explained as either a facilitator or barrier to policy implementation. This theory was found as very useful in explaining policy implementation experiences of both policy makers and facilitators. CONCLUSION: A central tenet that was present in this context but not fully captured by CIT was leadership. Leadership interactions were revealed as critical for policy implementation, hence we propose the inclusion of leadership interactions to the current CIT central tenets, to become motivation, information, power, resources, leadership and interactions of all these.

Mortality Rate in a Cohort of People Living With HIV in Rural Tanzania After Accounting for Unseen Deaths Among Those Lost to Follow-up.

Mortality assessment in cohorts with high numbers of persons lost to follow-up (LTFU) is challenging in settings with limited civil registration systems. We aimed to assess mortality in a clinical cohort (the Kilombero and Ulanga Antiretroviral Cohort (KIULARCO)) of human immunodeficiency virus (HIV)-infected persons in rural Tanzania, accounting for unseen deaths among participants LTFU. We included adults enrolled in 2005-2015 and traced a nonrandom sample of those LTFU. We estimated mortality using Kaplan-Meier methods 1) with routinely captured data (method A), 2) crudely incorporating tracing data (method B), 3) weighting using tracing data to crudely correct for unobserved deaths among participants LTFU (method C), and 4) weighting using tracing data accounting for participant characteristics (method D). We investigated associated factors using proportional hazards models. Among 7,460 adults, 646 (9%) died, 883 (12%) transferred to other clinics, and 2,911 (39%) were LTFU. Of 2,010 (69%) traced participants, 325 (16%) were found: 131 (40%) had died and 130 (40%) had transferred. Five-year mortality estimates derived using the 4 methods were 13.1% (A), 16.2% (B), 36.8% (C), and 35.1% (D), respectively. Higher mortality was associated with male sex, referral as a hospital inpatient, living close to the index clinic, lower body mass index, more advanced World Health Organization HIV clinical stage, lower CD4 cell count, and less time since initiation of antiretroviral therapy. Adjusting for unseen deaths among participants LTFU approximately doubled the 5-year mortality estimates. Our approach is applicable to other cohort studies adopting targeted tracing.

Role of human Pegivirus infections in whole Plasmodium falciparum sporozoite vaccination and controlled human malaria infection in African volunteers.

BACKGROUND: Diverse vaccination outcomes and protection levels among different populations pose a serious challenge to the development of an effective malaria vaccine. Co-infections are among many factors associated with immune dysfunction and sub-optimal vaccination outcomes. Chronic, asymptomatic viral infections can contribute to the modulation of vaccine efficacy through various mechanisms. Human Pegivirus-1 (HPgV-1) persists in immune cells thereby potentially modulating immune responses. We investigated whether Pegivirus infection influences vaccine-induced responses and protection in African volunteers undergoing whole P. falciparum sporozoites-based malaria vaccination and controlled human malaria infections (CHMI). METHODS: HPgV-1 prevalence was quantified by RT-qPCR in plasma samples of 96 individuals before, post vaccination with PfSPZ Vaccine and after CHMI in cohorts from Tanzania and Equatorial Guinea. The impact of HPgV-1 infection was evaluated on (1) systemic cytokine and chemokine levels measured by Luminex, (2) PfCSP-specific antibody titers quantified by ELISA, (3) asexual blood-stage parasitemia pre-patent periods and parasite multiplication rates, (4) HPgV-1 RNA levels upon asexual blood-stage parasitemia induced by CHMI. RESULTS: The prevalence of HPgV-1 was 29.2% (28/96) and sequence analysis of the 5' UTR and E2 regions revealed the predominance of genotypes 1, 2 and 5. HPgV-1 infection was associated with elevated systemic levels of IL-2 and IL-17A. Comparable vaccine-induced anti-PfCSP antibody titers, asexual blood-stage multiplication rates and pre-patent periods were observed in HPgV-1 positive and negative individuals. However, a tendency for higher protection levels was detected in the HPgV-1 positive group (62.5%) compared to the negative one (51.6%) following CHMI. HPgV-1 viremia levels were not significantly altered after CHMI. CONCLUSIONS: HPgV-1 infection did not alter PfSPZ Vaccine elicited levels of PfCSP-specific antibody responses and parasite multiplication rates. Ongoing HPgV-1 infection appears to improve to some degree protection against CHMI in PfSPZ-vaccinated individuals. This is likely through modulation of immune system activation and systemic cytokines as higher levels of IL-2 and IL17A were observed in HPgV-1 infected individuals. CHMI is safe and well tolerated in HPgV-1 infected individuals. Identification of cell types and mechanisms of both silent and productive infection in individuals will help to unravel the biology of this widely present but largely under-researched virus.

Incidence of Plasmodium falciparum malaria infection in 6-month to 45-year-olds on selected areas of Bioko Island, Equatorial Guinea.

BACKGROUND: Extensive malaria control measures have been implemented on Bioko Island, Equatorial Guinea over the past 16 years, reducing parasite prevalence and malaria-related morbidity and mortality, but without achieving elimination. Malaria vaccines offer hope for reducing the burden to zero. Three phase 1/2 studies have been conducted successfully on Bioko Island to evaluate the safety and efficacy of whole Plasmodium falciparum (Pf) sporozoite (SPZ) malaria vaccines. A large, pivotal trial of the safety and efficacy of the radiation-attenuated Sanaria® PfSPZ Vaccine against P. falciparum is planned for 2022. This study assessed the incidence of malaria at the phase 3 study site and characterized the influence of socio-demographic factors on the burden of malaria to guide trial design. METHODS: A cohort of 240 randomly selected individuals aged 6 months to 45 years from selected areas of North Bioko Province, Bioko Island, was followed for 24 weeks after clearance of parasitaemia. Assessment of clinical presentation consistent with malaria and thick blood smears were performed every 2 weeks. Incidence of first and multiple malaria infections per person-time of follow-up was estimated, compared between age groups, and examined for associated socio-demographic risk factors. RESULTS: There were 58 malaria infection episodes observed during the follow up period, including 47 first and 11 repeat infections. The incidence of malaria was 0.25 [95% CI (0.19, 0.32)] and of first malaria was 0.23 [95% CI (0.17, 0.30)] per person per 24 weeks (0.22 in 6-59-month-olds, 0.26 in 5-17-year-olds, 0.20 in 18-45-year-olds). Incidence of first malaria with symptoms was 0.13 [95% CI (0.09, 0.19)] per person per 24 weeks (0.16 in 6-59-month-olds, 0.10 in 5-17-year-olds, 0.11 in 18-45-year-olds). Multivariate assessment showed that study area, gender, malaria positivity at screening, and household socioeconomic status independently predicted the observed incidence of malaria. CONCLUSION: Despite intensive malaria control efforts on Bioko Island, local transmission remains and is spread evenly throughout age groups. These incidence rates indicate moderate malaria transmission which may be sufficient to support future larger trials of PfSPZ Vaccine. The long-term goal is to conduct mass vaccination programmes to halt transmission and eliminate P. falciparum malaria.

Multisectoral Approach to Support Use of Insecticide-Treated Net for Malaria Prevention Among Mobile and Migrant Populations in Myanmar: A Systematic Review.

BACKGROUND: Myanmar is a premalaria elimination country with artemisinin-resistant malaria. A strategy for transmission control is focused on vulnerable groups such as mobile and migrant populations (MMPs), and includes improving access to insecticide-treated bed nets in the Myanmar artemisinin resistance containment (MARC) zones using multisectoral approaches (MSA). METHODS: This narrative systematic review addressed MSAs targeted to MMPs in Myanmar for malaria prevention. We searched relevant studies in electronic databases and present the narrative findings in 4 domains: stakeholder groups, net coverage and utilization, social determinates, and facilitators/barriers. RESULTS: Nine studies were included. The review identified stakeholders involved in intersectoral collaboration. Net ownership was higher than utilization rates in the MARC zones and rates remained below the WHO recommended target of 100%. There was inadequate description of roles and responsibilities for implementation and on channels of communication within the partnerships and with the Government. CONCLUSIONS: Findings show that interventions to distribute treated bed nets were supported by the multiple stakeholders. Due to the design of the primary studies, analysis of the added value of intersectoral collaboration was limited. More attention must be paid to designing studies to document and evaluate the contributions and outcomes of intersectoral collaboration.

Increase of Dose Associated With Decrease in Protection Against Controlled Human Malaria Infection by PfSPZ Vaccine in Tanzanian Adults.

BACKGROUND: A vaccine would be an ideal tool for reducing malaria's impact. PfSPZ Vaccine (radiation attenuated, aseptic, purified, cryopreserved Plasmodium falciparum [Pf] sporozoites [SPZ]) has been well tolerated and safe in >1526 malaria-naive and experienced 6-month to 65-year-olds in the United States, Europe, and Africa. When vaccine efficacy (VE) of 5 doses of 2.7 × 105 PfSPZ of PfSPZ Vaccine was assessed in adults against controlled human malaria infection (CHMI) in the United States and Tanzania and intense field transmission of heterogeneous Pf in Mali, Tanzanians had the lowest VE (20%). METHODS: To increase VE in Tanzania, we increased PfSPZ/dose (9 × 105 or 1.8 × 106) and decreased numbers of doses to 3 at 8-week intervals in a double blind, placebo-controlled trial. RESULTS: All 22 CHMIs in controls resulted in parasitemia by quantitative polymerase chain reaction. For the 9 × 105 PfSPZ group, VE was 100% (5/5) at 3 or 11 weeks (P < .000l, Barnard test, 2-tailed). For 1.8 × 106 PfSPZ, VE was 33% (2/6) at 7.5 weeks (P = .028). VE of dosage groups (100% vs 33%) was significantly different (P = .022). Volunteers underwent repeat CHMI at 37-40 weeks after last dose. 6/6 and 5/6 volunteers developed parasitemia, but time to first parasitemia was significantly longer than controls in the 9 × 105 PfSPZ group (10.89 vs 7.80 days) (P = .039), indicating a significant reduction in parasites in the liver. Antibody and T-cell responses were higher in the 1.8 × 106 PfSPZ group. CONCLUSIONS: In Tanzania, increasing the dose from 2.7 × 105 to 9 × 105 PfSPZ increased VE from 20% to 100%, but increasing to 1.8 × 106 PfSPZ significantly reduced VE. CLINICAL TRIALS REGISTRATION: NCT02613520.

History of malaria control in Rwanda: implications for future elimination in Rwanda and other malaria-endemic countries.

BACKGROUND: Malaria was first reported in Rwanda in the early 1900s with significant heterogeneity and volatility in transmission over subsequent decades. Here, a comprehensive literature review of malaria transmission patterns and control strategies in Rwanda between 1900 and 2018 is presented to provide insight into successes and challenges in the country and to inform the future of malaria control in Rwanda. METHODS: A systematic literature search of peer-reviewed publications (Web of Knowledge, PubMed, Google Scholar, and the World Health Organization Library (WHOLIS) and grey literature on malaria control in Rwanda between 1900 and 2019 was conducted with the following search terms: "malaria"", "Rwanda", "epidemiology", "control", "treatment", and/or "prevention." Reports and other relevant documents were also obtained from the Rwanda National Malaria Control Programme (NMCP). To inform this literature review and evidence synthesis, epidemiologic and intervention data were collated from NMCP and partner reports, the national routine surveillance system, and population surveys. RESULTS: Two hundred sixty-eight peer-reviewed publications and 56 grey literature items were reviewed, and information was extracted. The history of malaria control in Rwanda is thematically described here according to five phases: 1900 to 1954 before the launch of the Global Malaria Eradication Programme (GMEP); (2) Implementation of the GMEP from 1955 to 1969; (3) Post- GMEP to 1994 Genocide; (4) the re-establishment of malaria control from 1995 to 2005, and (5) current malaria control efforts from 2006 to 2018. The review shows that Rwanda was an early adopter of tools and approaches in the early 2000s, putting the country ahead of the curve and health systems reforms created an enabling environment for an effective malaria control programme. The last two decades have seen unprecedented investments in malaria in Rwanda, resulting in significant declines in disease burden from 2000 to 2011. However, in recent years, these gains appear to have reversed with increasing cases since 2012 although the country is starting to make progress again. CONCLUSION: The review shows the impact and fragility of gains against malaria, even in the context of sustained health system development. Also, as shown in Rwanda, country malaria control programmes should be dynamic and adaptive to respond and address changing settings.

Patterns of pesticide usage in agriculture in rural Tanzania call for integrating agricultural and public health practices in managing insecticide-resistance in malaria vectors.

BACKGROUND: Unrestricted use of pesticides in agriculture is likely to increase insecticide resistance in mosquito vectors. Unfortunately, strategies for managing insecticide resistance in agriculture and public health sectors lack integration. This study explored the types and usage of agricultural pesticides, and awareness and management practices among retailers and farmers in Ulanga and Kilombero districts in south-eastern Tanzania, where Anopheles mosquitoes are resistant to pyrethroids. METHODS: An exploratory sequential mixed-methods approach was employed. First, a survey to characterize pesticide stocks was conducted in agricultural and veterinary (agrovet) retail stores. Interviews to assess general knowledge and practices regarding agricultural pesticides were performed with 17 retailers and 30 farmers, followed by a survey involving 427 farmers. Concurrently, field observations were done to validate the results. RESULTS: Lambda-cyhalothrin, cypermethrin (both pyrethroids) and imidacloprids (neonicotinoids) were the most common agricultural insecticides sold to farmers. The herbicide glyphosate (amino-phosphonates) (59.0%), and the fungicides dithiocarbamate and acylalanine (54.5%), and organochlorine (27.3%) were also readily available in the agrovet shops and widely used by farmers. Although both retailers and farmers had at least primary-level education and recognized pesticides by their trade names, they lacked knowledge on pest control or proper usage of these pesticides. Most of the farmers (54.4%, n = 316) relied on instructions from pesticides dealers. Overall, 93.7% (400) farmers practised pesticides mixing in their farms, often in close proximity to water sources. One-third of the farmers disposed of their pesticide leftovers (30.0%, n = 128) and most farmers discarded empty pesticide containers into rivers or nearby bushes (55.7%, n = 238). CONCLUSION: Similarities of active ingredients used in agriculture and malaria vector control, poor pesticide management practices and low-levels of awareness among farmers and pesticides retailers might enhance the selection of insecticide resistance in malaria vectors. This study emphasizes the need for improving awareness among retailers and farmers on proper usage and management of pesticides. The study also highlights the need for an integrated approach, including coordinated education on pesticide use, to improve the overall management of insecticide resistance in both agricultural and public health sectors.

Reduced human-biting preferences of the African malaria vectors Anopheles arabiensis and Anopheles gambiae in an urban context: controlled, competitive host-preference experiments in Tanzania.

BACKGROUND: Host preference is a critical determinant of human exposure to vector-borne infections and the impact of vector control interventions. Widespread use of long-lasting insecticide-treated nets (LLINs) and indoor residual spraying (IRS) across sub-Saharan Africa, which protect humans against mosquitoes, may select for altered host preference traits of malaria vectors over the long term. Here, the host preferences of Anopheles arabiensis and Anopheles gambiae sensu stricto (s.s.) were experimentally assessed in the field, using direct host-preference assays in two distinct ecological settings in Tanzania. METHODS: Eight Ifakara Tent Trap (ITT), four baited with humans and four with bovine calves, were simultaneously used to catch malaria vectors in open field sites in urban and rural Tanzania. The numbers of mosquitoes collected in human-baited traps versus calf-baited traps were used to estimate human feeding preference for each site's vector species. RESULTS: The estimated proportion [95% confidence interval (CI)] of mosquitoes attacking humans rather than cattle was 0.60 [0.40, 0.77] for An. arabiensis in the rural setting and 0.61 [0.32, 0.85] for An. gambiae s.s. in the urban setting, indicating no preference for either host in both cases (P = 0.32 and 0.46, respectively) and no difference in preference between the two (Odds Ratio (OR) [95%] = 0.95 [0.30, 3.01], P = 0.924). However, only a quarter of An. arabiensis in the urban setting attacked humans (0.25 [0.09, 0.53]), indicating a preference for cattle that approached significance (P = 0.08). Indeed, urban An. arabiensis were less likely to attack humans rather than cattle when compared to the same species in the rural setting (OR [95%] = 0.21 [0.05, 0.91], P = 0.037). CONCLUSION: Urban An. arabiensis had a stronger preference for cattle than the rural population and urban An. gambiae s.s. showed no clear preference for either humans or cattle. In the urban setting, both species exhibited stronger tendencies to attack cattle than previous studies of the same species in rural contexts. Cattle keeping may, therefore, particularly limit the impact of human-targeted vector control interventions in Dar es Salaam and perhaps in other African towns and cities.

Effectiveness of the innovative 1,7-malaria reactive community-based testing and response (1, 7-mRCTR) approach on malaria burden reduction in Southeastern Tanzania.

BACKGROUND: In 2015, a China-UK-Tanzania tripartite pilot project was implemented in southeastern Tanzania to explore a new model for reducing malaria burden and possibly scaling-out the approach into other malaria-endemic countries. The 1,7-malaria Reactive Community-based Testing and Response (1,7-mRCTR) which is a locally-tailored approach for reporting febrile malaria cases in endemic villages was developed to stop transmission and Plasmodium life-cycle. The (1,7-mRCTR) utilizes existing health facility data and locally trained community health workers to conduct community-level testing and treatment. METHODS: The pilot project was implemented from September 2015 to June 2018 in Rufiji District, southern Tanzania. The study took place in four wards, two with low incidence and two with a higher incidence. One ward of each type was selected for each of the control and intervention arms. The control wards implemented the existing Ministry of Health programmes. The 1,7-mRCTR activities implemented in the intervention arm included community testing and treatment of malaria infection. Malaria case-to-suspect ratios at health facilities (HF) were aggregated by villages, weekly to identify the village with the highest ratio. Community-based mobile test stations (cMTS) were used for conducting mass testing and treatment. Baseline (pre) and endline (post) household surveys were done in the control and intervention wards to assess the change in malaria prevalence measured by the interaction term of 'time' (post vs pre) and arm in a logistic model. A secondary analysis also studied the malaria incidence reported at the HFs during the intervention. RESULTS: Overall the 85 rounds of 1,7-mRCTR conducted in the intervention wards significantly reduced the odds of malaria infection by 66% (adjusted OR 0.34, 95% CI 0.26,0.44, p < 0001) beyond the effect of the standard programmes. Malaria prevalence in the intervention wards declined by 81% (from 26% (95% CI 23.7, 7.8), at baseline to 4.9% (95% CI 4.0, 5.9) at endline). In villages receiving the 1,7-mRCTR, the short-term case ratio decreased by over 15.7% (95% CI - 33, 6) compared to baseline. CONCLUSION: The 1,7-mRCTR approach significantly reduced the malaria burden in the areas of high transmission in rural southern Tanzania. This locally tailored approach could accelerate malaria control and elimination efforts. The results provide the impetus for further evaluation of the effectiveness and scaling up of this approach in other high malaria burden countries in Africa, including Tanzania.

Ethical principles for promoting health research data sharing with sub-Saharan Africa.

A powerful feature of global health research is data-sharing with regions which bear the heaviest burden of disease. It offers novel opportunities for aggregating data to address critical global health challenges in ways higher than relying on individual studies. Yet there exist important stratifiers of the capacity to share data, particularly across the Global North-South divide. Systemic challenges that characterize sub-Saharan Africa and disadvantage the region's scientific productivity threaten the burgeoning data-sharing culture too. Like all endeavors requiring equal commitments under unequal circumstances, a strong ethical impetus is needed to help reduce inequities and imbalances to encourage adherence. This article discusses mandatory data-sharing in relation to peculiar challenges faced by sub-Saharan African scientists to suggest ethical principles for rethinking and reframing solutions. We propose six principles which mirror guidelines from the Institute of Medicine and encapsulate principles from the Emanuel Framework, Nairobi Data Sharing Principles, and the COHRED guidelines.

Clinical trials in low-resource settings: the perspectives of caregivers of paediatric participants from Uganda, Tanzania and Kenya.

OBJECTIVES: Vaccine clinical trials in low-resource settings have unique challenges due to structural and financial inequities. Specifically, protecting participant and caregiver autonomy to participate in the research study can be a major challenge, so understanding the setting and contextual factors which influence the decision process is necessary. This study investigates the experience of caregivers consenting on behalf of paediatric participants in a malaria vaccine clinical trial where participation enables access to free, high-quality medical care. METHODS: We interviewed a total of 78 caregivers of paediatric participants previously enrolled in a phase II or III malaria vaccine clinical trial in Uganda, Tanzania and Kenya. Interviews were qualitative and analysed using a thematic framework analysis focusing on the embodied caregiver in the political, economic and social reality. RESULTS: Caregivers of participants in this study made the decision to enrol their child based on economic, social and political factors that extended beyond the trial into the community and the home. The provision of health care was the dominant reason for participation. Respondents reported how social networks, rumours, hierarchal structures, financial constraints and family dynamics affected their experience with research. CONCLUSIONS: The provision of medical care was a powerful motivator for participation. Caregiver choice was limited by structural constraints and scarce financial resources. The decision to participate in research extended beyond individual consent and was embedded in community and domestic hierarchies. Future research should assess other contexts to determine how the choice to participate in research is affected when free medical care is offered.

OBJECTIFS: Les essais cliniques de vaccins dans les régions à faibles ressources présentent des défis uniques en raison d'iniquités structurelles et financières. En particulier, la protection de l'autonomie des participants et des soignants dans la participation à l'étude de recherche peut être un défi majeur. Il est donc nécessaire de comprendre le contexte et les facteurs contextuels qui influencent le processus de décision. Cette étude examine l'expérience de soignants consentants au nom de participants pédiatriques à un essai clinique de vaccin antipaludique où la participation permet l'accès à des soins médicaux gratuits et de haute qualité. MÉTHODES: Nous avons interviewé un total de 78 soignants de participants pédiatriques qui avaient participé à un essai clinique de vaccin antipaludique de phase II ou III en Ouganda, en Tanzanie et au Kenya. Les entretiens ont été qualitatifs et analysés à l'aide d'une analyse de cadre thématique centrée sur le soignant, en tenant compte de la réalité politique, économique et sociale. RÉSULTATS: Les soignants des participants à cette étude ont pris la décision d'inscrire leur enfant sur base de facteurs économiques, sociaux et politiques qui s'étendaient au-delà de l'essai dans la communauté et à la maison. La fourniture de soins de santé était la principale raison de la participation. Les répondants ont rapporté comment les réseaux sociaux, les rumeurs, les structures hiérarchiques, les contraintes financières et la dynamique familiale ont affecté leur expérience avec la recherche. CONCLUSIONS: La fourniture de soins médicaux était un puissant facteur de motivation pour la participation. Le choix du soignant était limité par des contraintes structurelles et les ressources financières limitées. La décision de participer à la recherche allait au-delà du consentement individuel et s'inscrivait dans les hiérarchies communautaires et domestiques. Les recherches futures devraient évaluer d'autres contextes afin de déterminer comment le choix de participer à la recherche est affecté par la gratuité des soins médicaux.

Two successful decades of Swiss collaborations to develop new anti-malarials.

Over the last two decades there has been a renaissance in the pipeline of new drugs targeting malaria, with the launch of new products that help save the lives of children throughout the world. In addition, there is a wealth of new molecules both entering and progressing through clinical development. These bring hope for a new generation of simpler and more effective cures that could overcome the emerging threat of drug resistance. In addition, there is hope that some of these medicines will have prophylactic activity and can be used to protect vulnerable populations, given the absence of a highly effective vaccine. Switzerland has played a key role in the development of these medicines. First, the country has a long history of understanding the biology of parasites and the pharmacology of drug responses through the leadership of the Swiss Tropical and Public Health Institute in Basel. Second, the highly successful Swiss pharmaceutical industry brings, beyond excellence, a strong interest in neglected diseases, building on work at Hoffmann-La Roche in the last century and with more recent products from Novartis and other Swiss companies. Third, the emergence of product-development-partnerships, in this case led by the Medicines for Malaria Venture, based in Geneva, has helped to catalyze the development of new medicines and bring the community together within Switzerland and beyond. Finally, this progress would not have been possible without the engagement of the Swiss people and the support of the federal government through the Swiss Agency for Development and Cooperation (SDC), the State Secretariat of Education, Research and Innovation (SERI) and the Swiss Republic and Canton of Geneva.

Prospects and strategies for malaria elimination in the Greater Mekong Sub-region: a qualitative study.

BACKGROUND: As malaria elimination becomes a goal in malaria-endemic nations, questions of feasibility become critical. This article explores the potential challenges associated with this goal and future strategies for malaria elimination in the Greater Mekong Sub-region. METHODS: Thirty-two semi-structured interviews were conducted with policy makers (n = 17) and principal investigators (n = 15) selected based on their involvement in malaria prevention, control and elimination in the GMS. Interviews were audio-recorded and transcribed for qualitative content (thematic) analysis using QSR NVivo. RESULTS: All respondents described current malaria control and elimination strategies, such as case detection and management, prevention and strengthening of surveillance systems as critical and of equal priority. Aware of the emergence of multi-drug resistance in the GMS, researchers and policy makers outlined the need for additional elimination tools. As opposed to a centralized strategy, more targeted and tailored approaches to elimination were recommended. These included targeting endemic areas, consideration for local epidemiology and malaria species, and strengthening the peripheral health system. A decline in malaria transmission could lead to complacency amongst funders and policy makers resulting in a reduction or discontinuation of support for malaria elimination. Strong commitment of policymakers combined with strict monitoring and supervision by funders were considered pivotal to successful elimination programmes. CONCLUSION: Against a backdrop of increasing anti-malarial resistance and decreasing choices of anti-malarial regimens, policy makers and researchers stressed the urgency of finding new malaria elimination strategies. There was consensus that multi-pronged strategies and approaches are needed, that no single potential tool/strategy can be appropriate to all settings. Hence there is a need to customize malaria control and elimination strategies based on the better surveillance data.