Characteristics of the Western Province, Zambia, trial site for evaluation of attractive targeted sugar baits for malaria vector control.

BACKGROUND: The attractive targeted sugar bait (ATSB) is a novel malaria vector control tool designed to attract and kill mosquitoes using a sugar-based bait, laced with oral toxicant. Western Province, Zambia, was one of three countries selected for a series of phase III cluster randomized controlled trials of the Westham ATSB Sarabi version 1.2. The trial sites in Kenya, Mali, and Zambia were selected to represent a range of different ecologies and malaria transmission settings across sub-Saharan Africa. This case study describes the key characteristics of the ATSB Zambia trial site to allow for interpretation of the results relative to the Kenya and Mali sites. METHODS: This study site characterization incorporates data from the trial baseline epidemiological and mosquito sugar feeding surveys conducted in 2021, as well as relevant literature on the study area. RESULTS: CHARACTERIZATION OF THE TRIAL SITE: The trial site in Zambia was comprised of 70 trial-designed clusters in Kaoma, Nkeyema, and Luampa districts. Population settlements in the trial site were dispersed across a large geographic area with sparsely populated villages. The overall population density in the 70 study clusters was 65.7 people per square kilometre with a total site population of 122,023 people living in a geographic area that covered 1858 square kilometres. However, the study clusters were distributed over a total area of approximately 11,728 square kilometres. The region was tropical with intense and seasonal malaria transmission. An abundance of trees and other plants in the trial site were potential sources of sugar meals for malaria vectors. Fourteen Anopheles species were endemic in the site and Anopheles funestus was the dominant vector, likely accounting for around 95% of all Plasmodium falciparum malaria infections. Despite high coverage of indoor residual spraying and insecticide-treated nets, the baseline malaria prevalence during the peak malaria transmission season was 50% among people ages six months and older. CONCLUSION: Malaria transmission remains high in Western Province, Zambia, despite coverage with vector control tools. New strategies are needed to address the drivers of malaria transmission in this region and other malaria-endemic areas in sub-Saharan Africa.

Defining operational research priorities to improve malaria control and elimination in sub-Saharan Africa: results from a country-driven research prioritization setting process.

BACKGROUND: In order to reignite gains and accelerate progress toward improved malaria control and elimination, policy, strategy, and operational decisions should be derived from high-quality evidence. The U.S. President's Malaria Initiative (PMI) Insights project together with the Université Cheikh Anta Diop of Dakar, Senegal, conducted a broad stakeholder consultation process to identify pressing evidence gaps in malaria control and elimination across sub-Saharan Africa (SSA), and developed a priority list of country-driven malaria operational research (OR) and programme evaluation (PE) topics to address these gaps. METHODS: Five key stakeholder groups were engaged in the process: national malaria programmes (NMPs), research institutions in SSA, World Health Organization (WHO) representatives in SSA, international funding agencies, and global technical partners who support malaria programme implementation and research. Stakeholders were engaged through individual or small group interviews and an online survey, and asked about key operational challenges faced by NMPs, pressing evidence gaps in current strategy and implementation guidance, and priority OR and PE questions to address the challenges and gaps. RESULTS: Altogether, 47 interviews were conducted with 82 individuals, and through the online survey, input was provided by 46 global technical partners. A total of 33 emergent OR and PE topics were identified through the consultation process and were subsequently evaluated and prioritized by an external evaluation committee of experts from NMPs, research institutions, and the WHO. The resulting prioritized OR and PE topics predominantly focused on generating evidence needed to close gaps in intervention coverage, address persistent challenges faced by NMPs in the implementation of core strategic interventions, and inform the effective deployment of new tools. CONCLUSION: The prioritized research list is intended to serve as a key resource for informing OR and PE investments, thereby ensuring future investments focus on generating the evidence needed to strengthen national strategies and programme implementation and facilitating a more coordinated and impactful approach to malaria operational research.

Burden of malaria in pregnancy among adolescent girls compared to adult women in 5 sub-Saharan African countries: A secondary individual participant data meta-analysis of 2 clinical trials.

BACKGROUND: Malaria is among the top causes of death in adolescent girls (10 to 19 years) globally. Adolescent motherhood is associated with increased risk of adverse maternal and neonatal outcomes. The interaction of malaria, adolescence, and pregnancy is especially relevant in malaria endemic areas, where rates of adolescent pregnancy are high. However, data on burden of malaria among adolescent girls are limited. This study aimed at investigating whether adolescent girls were at a greater risk of experiencing malaria-related outcomes in pregnancy-parasitaemia and clinical disease-than adult women. METHODS AND FINDINGS: An individual secondary participant-level meta-analysis was conducted using data from 5,804 pregnant women participating in 2 malaria prevention clinical trials in Benin, Gabon, Kenya, Mozambique, and Tanzania between 2009 and 2014. Of the sample, 1,201 participants were adolescent girls with a mean age of 17.5 years (standard deviation (SD) 1.3) and 886 (73.8%) of them primigravidae. Among the 4,603 adult women with mean age of 27.0 years (SD 5.4), 595 (12.9%) were primigravidae. Mean gestational age at enrolment was 20.2 weeks (SD 5.2) and 1,069 (18.4%) participants were HIV-infected. Women were followed monthly until the postpartum visit (1 month to 6 weeks after delivery). This study considered outcomes including clinical episodes during pregnancy, peripheral parasitaemia at delivery, and placental malaria. A 2-stage meta-analysis approach was followed by pooling single multivariable regression results into standard DerSimonian-Laird random-effects models. Adolescent girls were more likely than adult women to present with clinical malaria during pregnancy (incidence risk ratio (IRR) 1.70, 95% confidence interval (CI) 1.20; 2.39, p-value = 0.003, I2 = 0.0%, N = 4,092), peripheral parasitaemia at delivery (odds ratio (OR) 2.28, 95% CI 1.46; 3.55, p-value < 0.001, I2 = 0.0%, N = 3,977), and placental infection (OR 1.97, 95% CI 1.31; 2.98, p-value = 0.001, I2 = 1.4%, N = 4,797). Similar associations were observed among the subgroup of HIV-uninfected participants: IRR 1.72 (95% CI 1.22; 2.45, p-value = 0.002, I2 = 0.0%, N = 3,531) for clinical malaria episodes, OR 2.39 (95% CI 1.49; 3.86, p-value < 0.001, I2 = 0.0%, N = 3,053) for peripheral parasitaemia, and OR 1.88 (95% CI 1.06 to 3.33, p-value = 0.03, I2 = 34.9%, N = 3,847) for placental malaria. Among HIV-infected subgroups statistically significant associations were not observed. Similar associations were found in the subgroup analysis by gravidity. The small sample size and outcome prevalence in specific countries limited the inclusion of some countries in the meta-analysis. Furthermore, peripheral parasitaemia and placental malaria presented a considerable level of missing data-12.6% and 18.2% of participants had missing data on those outcomes, respectively. Given the original scope of the clinical trials, asymptomatic malaria infection was only assessed at the end of pregnancy through peripheral and placental parasitaemia. CONCLUSIONS: In this study, we observed that adolescent girls in sub-Saharan Africa (SSA) are more prone to experience clinical malaria episodes during pregnancy and have peripheral malaria and placental infection at delivery than adult women. Moreover, to the best of our knowledge, for the first time this study disaggregates figures and stratifies analyses by HIV infection. Similar associations were found for both HIV-infected and uninfected women, although those for HIV-infected participants were not statistically significant. Our finding suggests that adolescent girls may benefit from targeted malaria prevention strategies even before they become pregnant.

Reduced exposure to malaria vectors following indoor residual spraying of pirimiphos-methyl in a high-burden district of rural Mozambique with high ownership of long-lasting insecticidal nets: entomological surveillance results from a cluster-randomized trial.

BACKGROUND: The need to develop new products and novel approaches for malaria vector control is recognized as a global health priority. One approach to meeting this need has been the development of new products for indoor residual spraying (IRS) with novel active ingredients for public health. While initial results showing the impact of several of these next-generation IRS products have been encouraging, questions remain about how to best deploy them for maximum impact. To help address these questions, a 2-year cluster-randomized controlled trial to measure the impact of IRS with a microencapsulated formulation of pirimiphos-methyl (PM) in an area with high ownership of long-lasting insecticidal nets (LLINs) was conducted in a high-transmission district of central Mozambique with pyrethroid resistant vectors. Presented here are the results of the vector surveillance component of the trial. METHODS: The 2 year, two-armed trial was conducted in Mopeia District, Zambezia Province, Mozambique. In ten sentinel villages, five that received IRS with PM in October-November 2016 and again in October-November 2017 and five that received no IRS, indoor light trap collections and paired indoor-outdoor human landing collections catches (HLCs) were conducted monthly from September 2016 through October 2018. A universal coverage campaign in June 2017, just prior to the second spray round, distributed 131,540 standard alpha-cypermethrin LLINs across all study villages and increased overall net usage rates in children under 5 years old to over 90%. RESULTS: The primary malaria vector during the trial was Anopheles funestus sensu lato (s.l.), and standard World Health Organization (WHO) tube tests with this population indicated variable but increasing resistance to pyrethroids (including alpha-cypermethrin, from > 85% mortality in 2017 to 7% mortality in 2018) and uniform susceptibility to PM (100% mortality in both years). Over the entire duration of the study, IRS reduced An. funestus s.l. densities by 48% (CI95 33-59%; p < 0.001) in indoor light traps and by 74% (CI95 38-90%; p = 0.010) during indoor and outdoor HLC, though in each study year reductions in vector density were consistently greatest in those months immediately following the IRS campaigns and waned over time. Overall there was no strong preference for An. funestus to feed indoors or outdoors, and these biting behaviours did not differ significantly across study arms: observed indoor-outdoor biting ratios were 1.10 (CI95 1.00-1.21) in no-IRS villages and 0.88 (CI95 0.67-1.15) in IRS villages. The impact of IRS was consistent in reducing HLC exposures both indoors (75% reduction: CI95 47-88%; p = 0. < 0.001) and outdoors (68% reduction: CI95 22-87%; p = 0.012). While substantially fewer Anopheles gambiae s.l. were collected during the study, trends show a similar impact of IRS on this key vector group as well, with a 33% (CI95 7-53%; p = 0.019) reduction in mosquitoes collected in light traps and a non-statistically significant 39% reduction (p = 0.249) in HLC landing rates. CONCLUSION: IRS with PM used in addition to pyrethroid-only LLINs substantially reduced human exposures to malaria vectors during both years of the cluster-randomized controlled trial in Mopeia-a high-burden district where the primary vector, An. funestus s.l., was equally likely to feed indoors or outdoors and demonstrated increasing resistance to pyrethroids. Findings suggest that IRS with PM can provide effective vector control, including in some settings where pyrethroid-only ITNs are widely used. Trial registration clinicaltrials.gov , NCT02910934. Registered 22 September 2016, https://www.clinicaltrials.gov/ct2/show/NCT02910934.

A Public Health Paradox: The Women Most Vulnerable to Malaria Are the Least Protected.

Raquel Gonzalez and colleagues highlight an urgent need to evaluate antimalarials that can be safely administered to HIV-infected pregnant women on antiretroviral treatment and cotrimoxazole prophylaxis.

The central role of national programme management for the achievement of malaria elimination: a cross case-study analysis of nine malaria programmes.

BACKGROUND: A malaria eradication goal has been proposed, at the same time as a new global strategy and implementation framework. Countries are considering the strategies and tools that will enable progress towards malaria goals. The eliminating malaria case-study series reports were reviewed to identify successful programme management components using a cross-case study analytic approach. METHODS: Nine out of ten case-study reports were included in the analysis (Bhutan, Cape Verde, Malaysia, Mauritius, Namibia, Philippines, Sri Lanka, Turkey, Turkmenistan). A conceptual framework for malaria elimination programme management was developed and data were extracted and synthesized. Findings were reviewed at a consultative workshop, which led to a revision of the framework and further data extraction and synthesis. Success factors of implementation, programme choices and changes, and enabling factors were distilled. RESULTS: Decentralized programmes enhanced engagement in malaria elimination by sub-national units and communities. Integration of the malaria programme into other health services was also common. Decentralization and integration were often challenging due to the skill and experience levels of newly tasked staff. Accountability for programme impact was not clarified for most programmes. Motivation of work force was a key factor in maintaining programme quality but there were few clear, detailed strategies provided. Different incentive schemes targeted various stakeholders. Training and supervision, although not well described, were prioritized by most programmes. Multi-sectoral collaboration helped some programmes share information, build strategies and interventions and achieve a higher quality of implementation. In most cases programme action was spurred by malaria outbreaks or a new elimination goal with strong leadership. Some programmes showed high capacity for flexibility through introduction of new strategies and tools. Several case-studies described methods for monitoring implementation quality and coverage; however analysis and feedback to those implementing malaria elimination in the periphery was not well described. Political commitment and sustained financing contributed to malaria programme success. Consistency of malaria programmes depends on political commitment, human and financial resources, and leadership. Operational capacity of the programme and the overall health system structure and strength are also important aspects. CONCLUSIONS: Malaria eradication will require adaptive, well-managed malaria programmes that are able to tailor implementation of evidence-based strategies, founded upon strong sub-national surveillance and response, with adequate funding and human resources.

Strategies and approaches to vector control in nine malaria-eliminating countries: a cross-case study analysis.

BACKGROUND: There has been progress towards malaria elimination in the last decade. In response, WHO launched the Global Technical Strategy (GTS), in which vector surveillance and control play important roles. Country experiences in the Eliminating Malaria Case Study Series were reviewed to identify success factors on the road to elimination using a cross-case study analytic approach. METHODS: Reports were included in the analysis if final English language draft reports or publications were available at the time of analysis (Bhutan, Cape Verde, Malaysia, Mauritius, Namibia, Philippines, Sri Lanka, Turkey, Turkmenistan). A conceptual framework for vector control in malaria elimination was developed, reviewed, formatted as a matrix, and case study data was extracted and entered into the matrix. A workshop was convened during which participants conducted reviews of the case studies and matrices and arrived at a consensus on the evidence and lessons. The framework was revised and a second round of data extraction, synthesis and summary of the case study reports was conducted. RESULTS: Countries implemented a range of vector control interventions. Most countries aligned with integrated vector management, however its impact was not well articulated. All programmes conducted entomological surveillance, but the response (i.e., stratification and targeting of interventions, outbreak forecasting and strategy) was limited or not described. Indoor residual spraying (IRS) was commonly used by countries. There were several examples of severe reductions or halting of IRS coverage and subsequent resurgence of malaria. Funding and operational constraints and poor implementation had roles. Bed nets were commonly used by most programmes; coverage and effectiveness were either not measured or not articulated. Larval control was an important intervention for several countries, preventing re-introduction, however coverage and impact on incidence were not described. Across all interventions, coverage indicators were incomparable, and the rationale for which tools were used and which were not used appeared to be a function of the availability of funding, operational issues and cost instead of evidence of effectiveness to reduce incidence. CONCLUSIONS: More work is required to fill gaps in programme guidance, clarify the best methods for choosing and targeting vector control interventions, and support to measure cost, cost-effectiveness and cost-benefit of vector surveillance and control interventions.

Malaria vector research and control in Haiti: a systematic review.

BACKGROUND: Haiti has a set a target of eliminating malaria by 2020. However, information on malaria vector research in Haiti is not well known. This paper presents results from a systematic review of the literature on malaria vector research, bionomics and control in Haiti. METHODS: A systematic search of literature published in French, Spanish and English languages was conducted in 2015 using Pubmed (MEDLINE), Google Scholar, EMBASE, JSTOR WHOLIS and Web of Science databases as well other grey literature sources such as USAID, and PAHO. The following search terms were used: malaria, Haiti, Anopheles, and vector control. RESULTS: A total of 132 references were identified with 40 high quality references deemed relevant and included in this review. Six references dealt with mosquito distribution, seven with larval mosquito ecology, 16 with adult mosquito ecology, three with entomological indicators of malaria transmission, eight with insecticide resistance, one with sero-epidemiology and 16 with vector control. In the last 15 years (2000-2015), there have only been four published papers and three-scientific meeting abstracts on entomology for malaria in Haiti. Overall, the general literature on malaria vector research in Haiti is limited and dated. DISCUSSION: Entomological information generated from past studies in Haiti will contribute to the development of strategies to achieve malaria elimination on Hispaniola. However it is of paramount importance that malaria vector research in Haiti is updated to inform decision-making for vector control strategies in support of malaria elimination.

Rapid response to Ebola outbreaks in remote areas - Liberia, July-November 2014.

West Africa is experiencing its first epidemic of Ebola virus disease (Ebola). As of February 9, Liberia has reported 8,864 Ebola cases, of which 3,147 were laboratory-confirmed. Beginning in August 2014, the Liberia Ministry of Health and Social Welfare (MOHSW), supported by CDC, the World Health Organization (WHO), and others, began systematically investigating and responding to Ebola outbreaks in remote areas. Because many of these areas lacked mobile telephone service, easy road access, and basic infrastructure, flexible and targeted interventions often were required. Development of a national strategy for the Rapid Isolation and Treatment of Ebola (RITE) began in early October. The strategy focuses on enhancing capacity of county health teams (CHT) to investigate outbreaks in remote areas and lead tailored responses through effective and efficient coordination of technical and operational assistance from the MOHSW central level and international partners. To measure improvements in response indicators and outcomes over time, data from investigations of 12 of 15 outbreaks in remote areas with illness onset dates of index cases during July 16-November 20, 2014, were analyzed. The times to initial outbreak alerts and durations of the outbreaks declined over that period while the proportions of patients who were isolated and treated increased. At the same time, the case-fatality rate in each outbreak declined. Implementation of strategies, such as RITE, to rapidly respond to rural outbreaks of Ebola through coordinated and tailored responses can successfully reduce transmission and improve outcomes.

The new global health.

Global health reflects the realities of globalization, including worldwide dissemination of infectious and noninfectious public health risks. Global health architecture is complex and better coordination is needed between multiple organizations. Three overlapping themes determine global health action and prioritization: development, security, and public health. These themes play out against a background of demographic change, socioeconomic development, and urbanization. Infectious diseases remain critical factors, but are no longer the major cause of global illness and death. Traditional indicators of public health, such as maternal and infant mortality rates no longer describe the health status of whole societies; this change highlights the need for investment in vital registration and disease-specific reporting. Noncommunicable diseases, injuries, and mental health will require greater attention from the world in the future. The new global health requires broader engagement by health organizations and all countries for the objectives of health equity, access, and coverage as priorities beyond the Millennium Development Goals are set.

It is time to rethink tactics in the fight against malaria.

April 25 marks World Malaria Day, an opportunity for those who work to defeat the illness, to review progress and renew commitments. After a decade of steady success, this year's commemoration of the date is also an opportunity to reconsider current approaches and assess the state of the science needed to keep pace in the global effort to combat malaria.

A randomized trial of artemether-lumefantrine and dihydroartemisinin-piperaquine in the treatment of uncomplicated malaria among children in western Kenya.

BACKGROUND: Artemether-lumefantrine (AL) was adopted as first-line treatment for uncomplicated malaria in Kenya in 2006. Monitoring drug efficacy at regular intervals is essential to prevent unnecessary morbidity and mortality. The efficacy of AL and dihydroartemisinin-piperaquine (DP) were evaluated for the treatment of uncomplicated malaria in children aged six to 59 months in western Kenya. METHODS: From October 2010 to August 2011, children with fever or history of fever with uncomplicated Plasmodium falciparum mono-infection were enrolled in an in vivo efficacy trial in accordance with World Health Organization (WHO) guidelines. The children were randomized to treatment with a three-day course of AL or DP and efficacy outcomes were measured at 28 and 42 days after treatment initiation. RESULTS: A total of 137 children were enrolled in each treatment arm. There were no early treatment failures and all children except one had cleared parasites by day 3. Polymerase chain reaction (PCR)-uncorrected adequate clinical and parasitological response rate (ACPR) was 61% in the AL arm and 83% in the DP arm at day 28 (p = 0.001). PCR-corrected ACPR at day 28 was 97% in the AL group and 99% in the DP group, and it was 96% in both arms at day 42. CONCLUSIONS: AL and DP remain efficacious for the treatment of uncomplicated malaria among children in western Kenya. The longer half-life of piperaquine relative to lumefantrine may provide a prophylactic effect, accounting for the lower rate of re-infection in the first 28 days after treatment in the DP arm.

Combination of probenecid-sulphadoxine-pyrimethamine for intermittent preventive treatment in pregnancy.

The antifolate sulphadoxine-pyrimethamine (SP) has been used in the intermittent prevention of malaria in pregnancy (IPTp). SP is an ideal choice for IPTp, however, as resistance of Plasmodium falciparum to SP increases, data are accumulating that SP may no longer provide benefit in areas of high-level resistance. Probenecid was initially used as an adjunctive therapy to increase the blood concentration of penicillin; it has since been used to augment concentrations of other drugs, including antifolates. The addition of probenecid has been shown to increase the treatment efficacy of SP against malaria, suggesting that the combination of probenecid plus SP may prolong the useful lifespan of SP as an effective agent for IPTp. Here, the literature on the pharmacokinetics, adverse reactions, interactions and available data on the use of these drugs in pregnancy is reviewed, and the possible utility of an SP-probenecid combination is discussed. This article concludes by calling for further research into this potentially useful combination.

Operational strategies to achieve and maintain malaria elimination.

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.

Review of mass drug administration for malaria and its operational challenges.

Mass drug administration (MDA) was a component of many malaria programs during the eradication era, but later was seldomly deployed due to concerns regarding efficacy and feasibility and fear of accelerating drug resistance. Recently, however, there has been renewed interest in the role of MDA as an elimination tool. Following a 2013 Cochrane Review that focused on the quantitative effects of malaria MDA, we have conducted a systematic, qualitative review of published, unpublished, and gray literature documenting past MDA experiences. We have also consulted with field experts, using their historical experience to provide an informed, contextual perspective on the role of MDA in malaria elimination. Substantial knowledge gaps remain and more research is necessary, particularly on optimal target population size, methods to improve coverage, and primaquine safety. Despite these gaps, MDA has been used successfully to control and eliminate Plasmodium falciparum and P. vivax malaria in the past, and should be considered as part of a comprehensive malaria elimination strategy in specific settings.

The combination of indoor residual spraying and insecticide-treated nets provides added protection against malaria compared with insecticide-treated nets alone.

Both insecticide-treated bed nets (ITNs) and indoor residual spraying (IRS) reduce malaria in high malaria transmission areas. The combined effect of these interventions is unknown. We conducted a non-randomized prospective cohort study to determine protective efficacy of IRS with ITNs (ITN + IRS) compared with ITNs alone (ITN only) in preventing Plasmodium falciparum parasitemia. At baseline, participants provided blood samples for malaria smears, were presumptively treated for malaria, and received ITNs. Blood smears were made monthly and at sick visits. In total, 1,804 participants were enrolled. Incidence of P. falciparum parasitemia in the ITN + IRS and ITN only groups was 18 and 44 infections per 100 persons-years at risk, respectively (unadjusted rate ratio = 0.41; 95% confidence interval [CI] = 0.31-0.56). Adjusted protective efficacy of ITN + IRS compared with ITN only was 62% (95% CI = 0.50-0.72). The combination of IRS and ITN might be a feasible strategy to further reduce malaria transmission in areas of persistent perennial malaria transmission.