Publications by authors named "Laurence Slutsker"

162 Publications

Tracking severe malaria disease.

Science 2021 08;373(6557):855-856

Department of Osteopathic Medical Specialties, College of Osteopathic Medicine, Michigan State University, 909 Wilson Road, East Lansing, MI 48824, USA.

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http://dx.doi.org/10.1126/science.abk3443DOI Listing
August 2021

Baseline Asymptomatic Malaria Infection and Immunogenicity of rVSVΔG-ZEBOV-GP Vaccine: The Sierra Leone Trial to Introduce a Vaccine Against Ebola (STRIVE).

J Infect Dis 2021 May 20. Epub 2021 May 20.

Centers for Disease Control and Prevention, Atlanta, GA, 30329-4027 USA.

Background: The effect of malaria infection on rVSVΔG-ZEBOV-GP (ERVEBO®) immunogenicity is unknown.

Methods: The Sierra Leone Trial to Introduce a Vaccine against Ebola (STRIVE) vaccinated 7998 asymptomatic adults with rVSVΔG-ZEBOV-GP during the 2014-6 Ebola epidemic. In STRIVE's immunogenicity sub-study, participants provided blood samples at baseline, 1, 6, and 9-12 months. Anti-glycoprotein (GP) binding and neutralizing antibodies were measured using validated assays. Baseline samples were tested for malaria parasites by PCR.

Results: Overall, 506 participants enrolled in the immunogenicity sub-study and had ≥1 post-vaccination antibody titer. Of 499 participants with a result, baseline malaria parasitemia was detected in 73(14.6%). All GP-ELISA and plaque reduction neutralization test (PRNT) geometric mean titers (GMTs) at 1, 6, and 9-12 months were above baseline, and 94.1% of participants seroresponded by GP-ELISA (≥2-fold rise AND ≥200 EU/ml), while 81.5% seroresponded by PRNT (≥4-fold rise) at ≥1 post-vaccination assessment. In participants with baseline malaria parasitemia, the PRNT seroresponse proportion was lower, while PRNT GMTs and GP-ELISA seroresponse and GMTs showed a trend toward lower responses at 6 and 9-12 months.

Conclusion: Asymptomatic adults with and without malaria parasitemia had robust immune responses to rVSVΔG-ZEBOV-GP persisting for 9-12 months. Responses in those with malaria parasitemia were somewhat lower.
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http://dx.doi.org/10.1093/infdis/jiab243DOI Listing
May 2021

Development of a new barcode-based, multiplex-PCR, next-generation-sequencing assay and data processing and analytical pipeline for multiplicity of infection detection of Plasmodium falciparum.

Malar J 2021 Feb 16;20(1):92. Epub 2021 Feb 16.

Division of Parasitic Diseases, Center for Global Health, Centers for Disease Control and Prevention (CDC), Atlanta, USA.

Background: Simultaneous infection with multiple malaria parasite strains is common in high transmission areas. Quantifying the number of strains per host, or the multiplicity of infection (MOI), provides additional parasite indices for assessing transmission levels but it is challenging to measure accurately with current tools. This paper presents new laboratory and analytical methods for estimating the MOI of Plasmodium falciparum.

Methods: Based on 24 single nucleotide polymorphisms (SNPs) previously identified as stable, unlinked targets across 12 of the 14 chromosomes within P. falciparum genome, three multiplex PCRs of short target regions and subsequent next generation sequencing (NGS) of the amplicons were developed. A bioinformatics pipeline including B4Screening pathway removed spurious amplicons to ensure consistent frequency calls at each SNP location, compiled amplicons by SNP site diversity, and performed algorithmic haplotype and strain reconstruction. The pipeline was validated by 108 samples generated from cultured-laboratory strain mixtures in different proportions and concentrations, with and without pre-amplification, and using whole blood and dried blood spots (DBS). The pipeline was applied to 273 smear-positive samples from surveys conducted in western Kenya, then providing results into StrainRecon Thresholding for Infection Multiplicity (STIM), a novel MOI estimator.

Results: The 24 barcode SNPs were successfully identified uniformly across the 12 chromosomes of P. falciparum in a sample using the pipeline. Pre-amplification and parasite concentration, while non-linearly associated with SNP read depth, did not influence the SNP frequency calls. Based on consistent SNP frequency calls at targeted locations, the algorithmic strain reconstruction for each laboratory-mixed sample had 98.5% accuracy in dominant strains. STIM detected up to 5 strains in field samples from western Kenya and showed declining MOI over time (q < 0.02), from 4.32 strains per infected person in 1996 to 4.01, 3.56 and 3.35 in 2001, 2007 and 2012, and a reduction in the proportion of samples with 5 strains from 57% in 1996 to 18% in 2012.

Conclusion: The combined approach of new multiplex PCRs and NGS, the unique bioinformatics pipeline and STIM could identify 24 barcode SNPs of P. falciparum correctly and consistently. The methodology could be applied to field samples to reliably measure temporal changes in MOI.
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http://dx.doi.org/10.1186/s12936-021-03624-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7885407PMC
February 2021

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.

Malar J 2021 Jan 21;20(1):54. Epub 2021 Jan 21.

PATH, Washington, DC, USA.

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% (CI 33-59%; p < 0.001) in indoor light traps and by 74% (CI 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 (CI 1.00-1.21) in no-IRS villages and 0.88 (CI 0.67-1.15) in IRS villages. The impact of IRS was consistent in reducing HLC exposures both indoors (75% reduction: CI 47-88%; p = 0. < 0.001) and outdoors (68% reduction: CI 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% (CI 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.
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http://dx.doi.org/10.1186/s12936-021-03583-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7819201PMC
January 2021

Rapid reduction of malaria transmission following the introduction of indoor residual spraying in previously unsprayed districts: an observational analysis of Mopti Region, Mali, in 2017.

Malar J 2020 Sep 19;19(1):340. Epub 2020 Sep 19.

PATH, Washington, DC, USA.

Background: The National Malaria Control Programme (NMCP) of Mali has had recent success decreasing malaria transmission using 3rd generation indoor residual spraying (IRS) products in areas with pyrethroid resistance, primarily in Ségou and Koulikoro Regions. In 2015, national survey data showed that Mopti Region had the highest under 5-year-old (u5) malaria prevalence at 54%-nearly twice the national average-despite having high access to long-lasting insecticidal nets (LLINs) and seasonal malaria chemoprevention (SMC). Accordingly, in 2016 the NMCP and other stakeholders shifted IRS activities from Ségou to Mopti. Here, the results of a series of observational analyses utilizing routine malaria indicators to evaluate the impact of this switch are presented.

Methods: A set of retrospective, eco-observational time-series analyses were performed using monthly incidence rates of rapid diagnostic test (RDT)-confirmed malaria cases reported in the District Health Information System 2 (DHIS2) from January 2016 until February 2018. Comparisons of case incidence rates were made between health facility catchments from the same region that differed in IRS status (IRS vs. no-IRS) to describe the general impact of the 2016 and 2017 IRS campaigns, and a difference-in-differences approach comparing changes in incidence from year-to-year was used to describe the effect of suspending IRS operations in Ségou and introducing IRS operations in Mopti in 2017.

Results: Compared to communities with no IRS, cumulative case incidence rates in IRS communities were reduced 16% in Ségou Region during the 6 months following the 2016 campaign and 31% in Mopti Region during the 6 months following the 2017 campaign, likely averting a total of more than 22,000 cases of malaria that otherwise would have been expected during peak transmission months. Across all comparator health facilities (HFs) where there was no IRS in either year, peak malaria case incidence rates fell by an average of 22% (CI 18-30%) from 2016 to 2017. At HFs in communities of Mopti where IRS was introduced in 2017, peak incidence fell by an average of 42% (CI 31-63%) between these years, a significantly greater decrease (p = 0.040) almost double what was seen in the comparator HFCAs. The opposite effect was observed in Ségou Region, where peak incidence at those HFs where IRS was withdrawn after the 2016 campaign increased by an average of 106% (CI 63-150%) from year to year, also a significant difference-in-differences compared to the comparator no-IRS HFs (p < 0.0001).

Conclusion: Annual IRS campaigns continue to make dramatic contributions to the seasonal reduction of malaria transmission in communities across central Mali, where IRS campaigns were timed in advance of peak seasonal transmission and utilized a micro-encapsulated product with an active ingredient that was of a different class than the one found on the LLINs used throughout the region and to which local malaria vectors were shown to be susceptible. Strategies to help mitigate the resurgence of malaria cases that can be expected should be prioritized whenever the suspension of IRS activities in a particular region is considered.
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http://dx.doi.org/10.1186/s12936-020-03414-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7501620PMC
September 2020

Combining next-generation indoor residual spraying and drug-based malaria control strategies: observational evidence of a combined effect in Mali.

Malar J 2020 Aug 15;19(1):293. Epub 2020 Aug 15.

PATH, Washington, DC, USA.

Background: Ségou Region in central Mali is an area of high malaria burden with seasonal transmission. The region reports high access to and use of long-lasting insecticidal nets (LLINs), though the principal vector, Anopheles gambiae, is resistant to pyrethroids. From 2011 until 2016, several high-burden districts of Ségou also received indoor residual spraying (IRS), though in 2014 concerns about pyrethroid resistance prompted a shift in IRS products to a micro-encapsulated formulation of the organophosphate insecticide pirimiphos-methyl. Also in 2014, the region expanded a pilot programme to provide seasonal malaria chemoprevention (SMC) to children aged 3-59 months in two districts. The timing of these decisions presented an opportunity to estimate the impact of both interventions, deployed individually and in combination, using quality-assured passive surveillance data.

Methods: A non-randomized, quasi-experimental time series approach was used to analyse monthly trends in malaria case incidence at the district level. Districts were stratified by intervention status: an SMC district, an IRS district, an IRS + SMC district, and control districts that received neither IRS nor SMC in 2014. The numbers of positive rapid diagnostic test (RDT +) results reported at community health facilities were aggregated and epidemiological curves showing the incidence of RDT-confirmed malaria cases per 10,000 person-months were plotted for the total all-ages and for the under 5 year old (u5) population. The cumulative incidence of RDT + malaria cases observed from September 2014 to February 2015 was calculated in each intervention district and compared to the cumulative incidence reported from the same period in the control districts.

Results: Cumulative peak-transmission all-ages incidence was lower in each of the intervention districts compared to the control districts: 16% lower in the SMC district; 28% lower in the IRS district; and 39% lower in the IRS + SMC district. The same trends were observed in the u5 population: incidence was 15% lower with SMC, 48% lower with IRS, and 53% lower with IRS + SMC. The SMC-only intervention had a more moderate effect on incidence reduction initially, which increased over time. The IRS-only intervention had a rapid, comparatively large impact initially that waned over time. The impact of the combined interventions was both rapid and longer lasting.

Conclusion: Evaluating the impact of IRS with an organophosphate and SMC on reducing incidence rates of passive RDT-confirmed malaria cases in Ségou Region in 2014 suggests that combining the interventions had a greater effect than either intervention used individually in this high-burden region of central Mali with pyrethroid-resistant vectors and high rates of household access to LLINs.
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http://dx.doi.org/10.1186/s12936-020-03361-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7429948PMC
August 2020

An observational analysis of the impact of indoor residual spraying in Northern, Upper East, and Upper West Regions of Ghana: 2014 through 2017.

Malar J 2020 Jul 11;19(1):242. Epub 2020 Jul 11.

PATH, Washington, DC, USA.

Background: Ghana has been implementing the indoor residual spraying (IRS) of insecticides since 2006, focusing operations in the north. Insecticide resistance concerns prompted a switch from pyrethroids to organophosphates, beginning gradually in 2011 and switching fully to the micro-encapsulated formulation of pirimiphosmethyl (PM CS), Actellic 300CS, a third-generation indoor residual spraying (3GIRS) product, by 2014. Entomological surveillance studies have shown IRS to be a highly effective malaria control tool, but epidemiological evidence is needed as well. Countrywide prevalence surveys have shown that malaria parasite prevalence in children under 5 years of age in Northern, Upper East, and Upper West Regions had declined to less than 40% in each region by 2016. Similarly, malaria deaths in children under 5 years of age have also been declining nationally since 2009. Although IRS is suspected to have contributed to this decline, stronger evidence is needed to link the IRS interventions to the epidemiological impact.

Methods: To assess the epidemiological impact of Ghana's IRS programmatic activities, a retrospective, observational analysis using routine epidemiological data was conducted to compare malaria incidence rates from IRS and non-IRS districts in Northern, Upper East, and Upper West Regions. Routine epidemiological data consisted of passive malaria case surveillance data reported in the District Health Information System 2 (DHIS2); with cases representing patients with suspected malaria who had sought care in the public health system and had received a confirmatory diagnosis with a positive malaria RDT result. Final routine data were extracted in September 2018. All districts that had received IRS were included in the analysis and compared to all non-IRS districts within the same region. In the Northern Region, only PMI districts were included in the analysis, as they had similar historical data.

Results: District-level analysis from Northern Region from 2015 to 2017 of the aggregate malaria incidence reported from IRS districts relative to non-IRS comparator districts showed 39%, 26%, and 58% fewer confirmed malaria cases reported from IRS districts in 2015, 2016, and 2017, respectively. This translates to approximately 257,000 fewer cases than expected over the three years. In Upper East Region, the effect on reported malaria cases of withdrawing IRS from the region was striking; after spray operations were suspended in 2015, incidence increased an average of 485% per district (95% confidence interval: 330% to 640%) compared to 2014.

Conclusions: The current observational analysis results are in line with the entomological studies in demonstrating the positive contribution of IRS with a 3GIRS product to malaria control programmes in northern Ghana and the value of using routine surveillance and implementation data to rapidly assess the impact of vector control interventions in operational settings, even in complex implementation environments.
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http://dx.doi.org/10.1186/s12936-020-03318-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7353711PMC
July 2020

Moving from Malaria Burden Reduction toward Elimination: An Evaluation of Mass Drug Administration in Southern Province, Zambia.

Am J Trop Med Hyg 2020 08;103(2_Suppl):3-6

National Malaria Control Centre, Zambia Ministry of Health, Lusaka, Zambia.

From December 2014 to February 2016, a cluster randomized controlled trial was carried out in 60 health facility catchment areas along Lake Kariba in Zambia's Southern Province. The trial sought to evaluate the impact of four rounds of a mass drug administration (MDA) intervention with dihydroartemisinin-piperaquine (DHAP) or focal MDA with DHAP at the household level compared with a control population that received the standard of care. This study was the first randomized controlled trial with DHAP for MDA in sub-Saharan Africa and was conducted through a collaboration between the National Malaria Elimination Programme in the Zambian Ministry of Health, the PATH Malaria Control and Elimination Partnership in Africa, and the Center for Applied Malaria Research and Evaluation at Tulane University. This article serves as an introduction to a collection of articles designed to explore different aspects of the intervention. By describing the recent history of malaria control in Zambia leading up to the trial-from the scale-up of point-of-care diagnosis and treatment, vector control, and indoor residual spraying early in the twenty-first century, to the efforts made to sustain the gains achieved with that approach-it provides a rationale for the implementation of a trial that has informed a new national strategic plan and solidified malaria elimination as Zambia's national goal.
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http://dx.doi.org/10.4269/ajtmh.19-0669DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7416971PMC
August 2020

Impact of Four Rounds of Mass Drug Administration with Dihydroartemisinin-Piperaquine Implemented in Southern Province, Zambia.

Am J Trop Med Hyg 2020 08;103(2_Suppl):7-18

PATH Malaria Control and Elimination Partnership in Africa (MACEPA), Lusaka, Zambia.

Over the past decade, Zambia has made substantial progress against malaria and has recently set the ambitious goal of eliminating by 2021. In the context of very high vector control and improved access to malaria diagnosis and treatment in Southern Province, we implemented a community-randomized controlled trial to assess the impact of four rounds of community-wide mass drug administration (MDA) and household-level MDA (focal MDA) with dihydroartemisinin-piperaquine (DHAP) implemented between December 2014 and February 2016. The mass treatment campaigns achieved relatively good household coverage (63-79%), were widely accepted by the community (ranging from 87% to 94%), and achieved very high adherence to the DHAP regimen (81-96%). Significant declines in all malaria study end points were observed, irrespective of the exposure group, with the overall parasite prevalence during the peak transmission season declining by 87.2% from 31.3% at baseline to 4.0% in 2016 at the end of the trial. Children in areas of lower transmission (< 10% prevalence at baseline) that received four MDA rounds had a 72% (95% CI = 12-91%) reduction in malaria parasite prevalence as compared with those with the standard of care without any mass treatment. Mass drug administration consistently had the largest short-term effect size across study end points in areas of lower transmission following the first two MDA rounds. In the context of achieving very high vector control coverage and improved access to diagnosis and treatment for malaria, our results suggest that MDA should be considered for implementation in African settings for rapidly reducing malaria outcomes in lower transmission settings.
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http://dx.doi.org/10.4269/ajtmh.19-0659DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7416977PMC
August 2020

A Longitudinal Cohort to Monitor Malaria Infection Incidence during Mass Drug Administration in Southern Province, Zambia.

Am J Trop Med Hyg 2020 08;103(2_Suppl):54-65

Department of Tropical Medicine, Center for Applied Malaria Research and Evaluation, Tulane University School of Public Health and Tropical Medicine, New Orleans, Louisiana.

Rigorous evidence of effectiveness is needed to determine where and when to apply mass drug administration (MDA) or focal MDA (fMDA) as part of a malaria elimination strategy. The Zambia National Malaria Elimination Centre recently completed a community-randomized controlled trial in Southern Province to evaluate MDA and fMDA for transmission reduction. To assess the role of MDA and fMDA on infection incidence, we enrolled a longitudinal cohort for an 18-month period of data collection including monthly malaria parasite infection detection based on polymerase chain reaction and compared time to first infection and cumulative infection incidence outcomes across study arms using Cox proportional hazards and negative binomial models. A total of 2,026 individuals from 733 households were enrolled and completed sufficient follow-up for inclusion in analysis. Infection incidence declined dramatically across all study arms during the period of study, and MDA was associated with reduced risk of first infection (hazards ratio: 0.36; 95% CI: 0.16-0.80) and cumulative infection incidence during the first rainy season (first 5 months of follow-up) (incidence rate ratio: 0.34; 95% CI: 0.12-0.95). No significant effect was found for fMDA or for either arm over the full study period. Polymerase chain reaction infection status at baseline was strongly associated with follow-up infection. The short-term effects of MDA suggest it may be an impactful accelerator of transmission reduction in areas with high coverage of case management and vector control and should be considered as part of a malaria elimination strategy.
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http://dx.doi.org/10.4269/ajtmh.19-0657DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7416973PMC
August 2020

Mass testing and treatment on malaria in an area of western Kenya.

Clin Infect Dis 2021 03;72(6):1103-1104

Malaria Branch, Division of Parasitic Diseases and Malaria, Center for Global Health, Centers for Disease Control and Prevention, Atlanta, Georgia, USA.

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http://dx.doi.org/10.1093/cid/ciaa813DOI Listing
March 2021

Impact of Community-Based Mass Testing and Treatment on Malaria Infection Prevalence in a High-Transmission Area of Western Kenya: A Cluster Randomized Controlled Trial.

Clin Infect Dis 2021 06;72(11):1927-1935

Malaria Branch, Division of Parasitic Diseases and Malaria, Center for Global Health, Centers for Disease Control and Prevention, Atlanta, Georgia, USA.

Background: Global gains toward malaria elimination have been heterogeneous and have recently stalled. Interventions targeting afebrile malaria infections may be needed to address residual transmission. We studied the efficacy of repeated rounds of community-based mass testing and treatment (MTaT) on malaria infection prevalence in western Kenya.

Methods: Twenty clusters were randomly assigned to 3 rounds of MTaT per year for 2 years or control (standard of care for testing and treatment at public health facilities along with government-sponsored mass long-lasting insecticidal net [LLIN] distributions). During rounds, community health volunteers visited all households in intervention clusters and tested all consenting individuals with a rapid diagnostic test. Those positive were treated with dihydroartemisinin-piperaquine. Cross-sectional community infection prevalence surveys were performed in both study arms at baseline and each year after 3 rounds of MTaT. The primary outcome was the effect size of MTaT on parasite prevalence by microscopy between arms by year, adjusted for age, reported LLIN use, enhanced vegetative index, and socioeconomic status.

Results: Demographic and behavioral characteristics, including LLIN usage, were similar between arms at each survey. MTaT coverage across the 3 annual rounds ranged between 75.0% and 77.5% in year 1, and between 81.9% and 94.3% in year 2. The adjusted effect size of MTaT on the prevalence of parasitemia between arms was 0.93 (95% confidence interval [CI], .79-1.08) and 0.92 (95% CI, .76-1.10) after year 1 and year 2, respectively.

Conclusions: MTaT performed 3 times per year over 2 years did not reduce malaria parasite prevalence in this high-transmission area.

Clinical Trials Registration: NCT02987270.
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http://dx.doi.org/10.1093/cid/ciaa471DOI Listing
June 2021

Malaria radical cure opportunity assessment in India: Discussing opportunities through stakeholder convening workshop and recommendation for improved access to malaria treatment.

J Vector Borne Dis 2020 Apr-Jun;57(2):182-186

PATH, Seattle, Washington, USA.

India contributes to over 40% of the global Plasmodium vivax disease burden, and P. vivax contributes to approximately one-third of all malaria in India. Government of India has set goals to eliminate malaria by 2030. Doing so will require scaling up existing and new strategies, treatments and diagnostic tools. Access to appropriate diagnosis and treatment for P. vivax malaria is currently limited, and it is unclear how new tools will be rolled out. To support the government in its malaria elimination efforts, the current challenges associated with access to best clinical management of vivax malaria must be understood and mitigated to effectively deploy new tools and scale up existing solutions. The recent Food and Drug Administration (US-FDA) as well as Therapeutics Goods Administration (Australian TGA) approval of tafenoquine, developed by GSK GlaxoSmithKline and Medicines for Malaria Venture (MMV) as a new single-dose radical cure treatment for P. vivax malaria, and the commercial availability of new point-of-care glucose-6-phosphate dehydrogenase (G6PD) tests provide new opportunities to improve clinical management of vivax malaria in India. This report discusses the background, objectives, implementation strategies, and next steps that came out of the Stakeholder Workshop on Malaria Radical Cure in New Delhi, India on 4 February 2019. The focus was to understand the risks and opportunities associated with access to best clinical practices for managing vivax malaria in India. A key outcome was to propose a framework for articulating and segmenting important investment opportunities for improving access to best clinical practices for P. vivax radical cure in India.
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http://dx.doi.org/10.4103/0972-9062.310865DOI Listing
July 2021

Community-based intermittent mass testing and treatment for malaria in an area of high transmission intensity, western Kenya: development of study site infrastructure and lessons learned.

Malar J 2019 Jul 29;18(1):255. Epub 2019 Jul 29.

Centers for Disease Control and Prevention (CDC), Atlanta, GA, USA.

Background: Malaria transmission is high in western Kenya and the asymptomatic infected population plays a significant role in driving the transmission. Mathematical modelling and simulation programs suggest that interventions targeting asymptomatic infections through mass testing and treatment (MTaT) or mass drug administration (MDA) have the potential to reduce malaria transmission when combined with existing interventions.

Objective: This paper describes the study site, capacity development efforts required, and lessons learned for implementing a multi-year community-based cluster-randomized controlled trial to evaluate the impact of MTaT for malaria transmission reduction in an area of high transmission in western Kenya.

Methods: The study partnered with Kenya's Ministry of Health (MOH) and other organizations on community sensitization and engagement to mobilize, train and deploy community health volunteers (CHVs) to deliver MTaT in the community. Within the health facilities, the study availed staff, medical and laboratory supplies and strengthened health information management system to monitor progress and evaluate impact of intervention.

Results: More than 80 Kenya MOH CHVs, 13 clinical officers, field workers, data and logistical staff were trained to carry out MTaT three times a year for 2 years in a population of approximately 90,000 individuals. A supply chain management was adapted to meet daily demands for large volumes of commodities despite the limitation of few MOH facilities having ideal storage conditions. Modern technology was adapted more to meet the needs of the high daily volume of collected data.

Conclusions: In resource-constrained settings, large interventions require capacity building and logistical planning. This study found that investing in relationships with the communities, local governments, and other partners, and identifying and equipping the appropriate staff with the skills and technology to perform tasks are important factors for success in delivering an intervention like MTaT.
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http://dx.doi.org/10.1186/s12936-019-2896-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6664589PMC
July 2019

Modelling the relationship between malaria prevalence as a measure of transmission and mortality across age groups.

Malar J 2019 Jul 23;18(1):247. Epub 2019 Jul 23.

Swiss Tropical and Public Health Institute, Basel, Switzerland.

Background: Parasite prevalence has been used widely as a measure of malaria transmission, especially in malaria endemic areas. However, its contribution and relationship to malaria mortality across different age groups has not been well investigated. Previous studies in a health and demographic surveillance systems (HDSS) platform in western Kenya quantified the contribution of incidence and entomological inoculation rates (EIR) to mortality. The study assessed the relationship between outcomes of malaria parasitaemia surveys and mortality across age groups.

Methods: Parasitological data from annual cross-sectional surveys from the Kisumu HDSS between 2007 and 2015 were used to determine malaria parasite prevalence (PP) and clinical malaria (parasites plus reported fever within 24 h or temperature above 37.5 °C). Household surveys and verbal autopsy (VA) were used to obtain data on all-cause and malaria-specific mortality. Bayesian negative binomial geo-statistical regression models were used to investigate the association of PP/clinical malaria with mortality across different age groups. Estimates based on yearly data were compared with those from aggregated data over 4 to 5-year periods, which is the typical period that mortality data are available from national demographic and health surveys.

Results: Using 5-year aggregated data, associations were established between parasite prevalence and malaria-specific mortality in the whole population (RR = 1.66; 95% Bayesian Credible Intervals: 1.07-2.54) and children 1-4 years (RR = 2.29; 1.17-4.29). While clinical malaria was associated with both all-cause and malaria-specific mortality in combined ages (RR = 1.32; 1.01-1.74); (RR = 2.50; 1.27-4.81), children 1-4 years (RR = 1.89; 1.00-3.51); (RR = 3.37; 1.23-8.93) and in older children 5-14 years (RR = 3.94; 1.34-11.10); (RR = 7.56; 1.20-39.54), no association was found among neonates, adults (15-59 years) and the elderly (60+ years). Distance to health facilities, socioeconomic status, elevation and survey year were important factors for all-cause and malaria-specific mortality.

Conclusion: Malaria parasitaemia from cross-sectional surveys was associated with mortality across age groups over 4 to 5 year periods with clinical malaria more strongly associated with mortality than parasite prevalence. This effect was stronger in children 5-14 years compared to other age-groups. Further analyses of data from other HDSS sites or similar platforms would be useful in investigating the relationship between malaria and mortality across different endemicity levels.
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http://dx.doi.org/10.1186/s12936-019-2869-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6651924PMC
July 2019

Short Communication: Reduced Nevirapine Concentrations Among HIV-Positive Women Receiving Mefloquine for Intermittent Preventive Treatment for Malaria Control During Pregnancy.

AIDS Res Hum Retroviruses 2018 11 17;34(11):912-915. Epub 2018 Oct 17.

3 Malaria Branch, Division of Parasitic Diseases and Malaria, Center for Global Health, Centers for Disease Control and Prevention , Atlanta, Georgia .

Clinical trials demonstrated intermittent preventive treatment in pregnancy with mefloquine (MQ) reduced malaria rates among pregnant women, yet an unexpected higher risk of mother-to-child transmission (MTCT) of HIV among HIV-positive women receiving MQ has also been observed. To determine if interactions between antiretroviral drugs (ARVs) and MQ could contribute to the increased MTCT observed in women receiving MQ, we performed a retrospective cross-sectional analysis of ARV plasma concentrations in peripheral blood (maternal plasma) and cord blood (cord plasma) collected at delivery from 186 mothers participating in a randomized clinical trial of MQ (n = 102) compared with placebo (n = 84) in Kenya. Plasma zidovudine (AZT), lamivudine (3TC), and nevirapine (NVP) concentrations were measured by high-performance liquid chromatography-tandem mass spectrometry. Although only 4% (7/186) reported not using these ARVs, AZT, 3TC, and NVP were all below the limit of detection in 44% of maternal plasma and 42% of cord plasma samples, and proportions were similar between the two study arms. Median concentrations of AZT and 3TC were not significantly lower in the MQ arm compared with the placebo arm for maternal plasma and cord plasma (p > .05). However, median NVP concentrations were significantly lower in the MQ study arm compared with the placebo study arm in both maternal plasma (1,597 ng/mL vs. 2,353 ng/mL, Mann-Whitney Rank Sum, p = .023) and cord plasma (2,038 ng/mL vs. 2,434 ng/mL, p = .048). Reduced NVP concentrations in maternal and cord plasma of women receiving MQ suggest MQ may affect NVP metabolism for both mother and infant. These results highlight the need to evaluate potential drug-drug interactions between candidate antimalarials and ARVs for use in pregnant women.
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http://dx.doi.org/10.1089/AID.2018.0042DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6238614PMC
November 2018

Factors Associated with the Rapid and Durable Decline in Malaria Incidence in El Salvador, 1980-2017.

Am J Trop Med Hyg 2018 07 10;99(1):33-42. Epub 2018 May 10.

PATH, Seattle, Washington.

A decade after the Global Malaria Eradication Program, El Salvador had the highest burden of malaria in Mesoamerica, with approximately 20% due to . A resurgence of malaria in the 1970s led El Salvador to alter its national malaria control strategy. By 1995, El Salvador recorded its last autochthonous case with fewer than 20 cases annually since 2011. By contrast, its immediate neighbors continue to have the highest incidences of malaria in the region. We reviewed and evaluated the policies and interventions implemented by the Salvadoran National Malaria Program that likely contributed to this progress toward malaria elimination. Decentralization of the malaria program, early regional stratification by risk, and data-driven stratum-specific actions resulted in the timely and targeted allocation of resources for vector control, surveillance, case detection, and treatment. Weekly reporting by health workers and volunteer collaborators-distributed throughout the country by strata and informed via the national surveillance system-enabled local malaria teams to provide rapid, adaptive, and focalized program actions. Sustained investments in surveillance and response have led to a dramatic reduction in local transmission, with most current malaria cases in El Salvador due to importation from neighboring countries. Additional support for systematic elimination efforts in neighboring countries would benefit the region and may be needed for El Salvador to achieve and maintain malaria elimination. El Salvador's experience provides a relevant case study that can guide the application of similar strategies in other countries committed to malaria elimination.
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http://dx.doi.org/10.4269/ajtmh.17-0629DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6085812PMC
July 2018

Association of maternal KIR gene content polymorphisms with reduction in perinatal transmission of HIV-1.

PLoS One 2018 23;13(1):e0191733. Epub 2018 Jan 23.

Division of Parasitic Diseases and Malaria, Center for Global Health, Centers for Disease Control and Prevention, Atlanta, Georgia, United States of America.

The role of killer cell immunoglobulin-like receptors (KIRs) in the transmission of HIV-1 has not been extensively studied. Here, we investigated the association of KIR gene content polymorphisms with perinatal HIV-1 transmission. The KIR gene family comprising 16 genes was genotyped in 313 HIV-1 positive Kenyan mothers paired with their infants. Gene content polymorphisms were presented as presence of individual KIR genes, haplotypes, genotypes and KIR gene concordance. The genetic data were analyzed for associations with perinatal transmission of HIV. There was no association of infant KIR genes with perinatal HIV-1 transmission. After adjustment for gravidity, viral load, and CD4 cell count, there was evidence of an association between reduction in perinatal HIV-1 transmission and the maternal individual KIR genes KIR2DL2 (adjusted OR = 0.50; 95% CI: 0.24-1.02, P = 0.06), KIR2DL5 (adjusted OR = 0.47; 95% CI: 0.23-0.95, P = 0.04) and KIR2DS5 (adjusted OR = 0.39; 95% CI: 0.18-0.80, P = 0.01). Furthermore, these maternal KIR genes were only significantly associated with reduction in perinatal HIV transmission in women with CD4 cell count ≥ 350 cells/ μl and viral load <10000 copies/ml. Concordance analysis showed that when both mother and child had KIR2DS2, there was less likelihood of perinatal HIV-1 transmission (adjusted OR = 0.44; 95% CI: 0.20-0.96, P = 0.039). In conclusion, the maternal KIR genes KIR2DL2, KIR2DL5, KIR2DS5, and KIR2DS2 were associated with reduction of HIV-1 transmission from mother to child. Furthermore, maternal immune status is an important factor in the association of KIR with perinatal HIV transmission.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0191733PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5779696PMC
February 2018

Infant and child mortality in relation to malaria transmission in KEMRI/CDC HDSS, Western Kenya: validation of verbal autopsy.

Malar J 2018 Jan 18;17(1):37. Epub 2018 Jan 18.

Swiss Tropical and Public Health Institute, Socinstr. 57, P.O. Box, 4002, Basel, Switzerland.

Background: Malaria transmission reduction is a goal of many malaria control programmes. Little is known of how much mortality can be reduced by specific reductions in transmission. Verbal autopsy (VA) is widely used for estimating malaria specific mortality rates, but does not reliably distinguish malaria from other febrile illnesses. Overall malaria attributable mortality includes both direct and indirect deaths. It is unclear what proportion of the deaths averted by reducing malaria transmission are classified as malaria in VA.

Methods: Both all-cause, and cause-specific mortality reported by VA for children under 5 years of age, were assembled from the KEMRI/CDC health and demographic surveillance system in Siaya county, rural Western Kenya for the years 2002-2004. These were linked to household-specific estimates of the Plasmodium falciparum entomological inoculation rate (EIR) based on high resolution spatio-temporal geostatistical modelling of entomological data. All-cause and malaria specific mortality (by VA), were analysed in relation to EIR, insecticide-treated net use (ITN), socioeconomic status (SES) and parameters describing space-time correlation. Time at risk for each child was analysed using Bayesian geostatistical Cox proportional hazard models, with time-dependent covariates. The outputs were used to estimate the diagnostic performance of VA in measuring mortality that can be attributed to malaria exposure.

Results: The overall under-five mortality rate was 80 per 1000 person-years during the study period. Eighty-one percent of the total deaths were assigned causes of death by VA, with malaria assigned as the main cause of death except in the neonatal period. Although no trend was observed in malaria-specific mortality assessed by VA, ITN use was associated with reduced all-cause mortality in infants (hazard ratio 0.15, 95% CI 0.02, 0.63) and the EIR was strongly associated with both all-cause and malaria-specific mortality. 48.2% of the deaths could be attributed to malaria by analysing the exposure-response relationship, though only 20.5% of VAs assigned malaria as the cause and the sensitivity of VAs was estimated to be only 26%. Although VAs assigned some deaths to malaria even in areas where there was estimated to be no exposure, the specificity of the VAs was estimated to be 85%.

Conclusion: Interventions that reduce P. falciparum transmission intensity will not only significantly reduce malaria-diagnosed mortality, but also mortality assigned to other causes in under-5 year old children in endemic areas. In this setting, the VA tool based on clinician review substantially underestimates the number of deaths that could be averted by reducing malaria exposure in childhood, but has a reasonably high specificity. This suggests that malaria transmission-reducing interventions such as ITNs can potentially reduce overall child mortality by as much as twice the total direct malaria burden estimated from VAs.
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http://dx.doi.org/10.1186/s12936-018-2184-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5774157PMC
January 2018

An observational analysis of the impact of indoor residual spraying with non-pyrethroid insecticides on the incidence of malaria in Ségou Region, Mali: 2012-2015.

Malar J 2018 01 10;17(1):19. Epub 2018 Jan 10.

PATH, Washington, DC, USA.

Background: Ségou Region in Central Mali is an area of high malaria burden with seasonal transmission, high access to and use of long-lasting insecticidal nets (LLINs), and resistance to pyrethroids and DDT well documented in Anopheles gambiae s.l. (the principal vector of malaria in Mali). Ségou has recently received indoor residual spraying (IRS) supported by Mali's collaboration with the US President's Malaria Initiative/Africa Indoor Residual Spraying programme. From 2012 to 2015, two different non-pyrethroid insecticides: bendiocarb in 2012 and 2013 and pirimiphos-methyl in 2014 and 2015, were used for IRS in two districts. This report summarizes the results of observational analyses carried out to assess the impact of these IRS campaigns on malaria incidence rates reported through local and district health systems before and after spraying.

Methods: A series of retrospective time series analyses were performed on 1,382,202 rapid diagnostic test-confirmed cases of malaria reported by district routine health systems in Ségou Region from January 2012 to January 2016. Malaria testing, treatment, surveillance and reporting activities remained consistent across districts and years during the study period, as did LLIN access and use estimates as well as An. gambiae s.l. insecticide resistance patterns. Districts were stratified by IRS implementation status and all-age monthly incidence rates were calculated and compared across strata from 2012 to 2014. In 2015 a regional but variable scale-up of seasonal malaria chemoprevention complicated the region-wide analysis; however IRS operations were suspended in Bla District that year so a difference in differences approach was used to compare 2014 to 2015 changes in malaria incidence at the health facility level in children under 5-years-old from Bla relative to changes observed in Barouéli, where IRS operations were consistent.

Results: During 2012-2014, rapid reductions in malaria incidence were observed during the 6 months following each IRS campaign, though most of the reduction in cases (70% of the total) was concentrated in the first 2 months after each campaign was completed. Compared to non-IRS districts, in which normal seasonal patterns of malaria incidence were observed, an estimated 286,745 total fewer cases of all-age malaria were observed in IRS districts. The total cost of IRS in Ségou was around 9.68 million USD, or roughly 33.75 USD per case averted. Further analysis suggests that the timing of the 2012-2014 IRS campaigns (spraying in July and August) was well positioned to maximize public health impact. Suspension of IRS in Bla District after the 2014 campaign resulted in a 70% increase in under-5-years-old malaria incidence rates from 2014 to 2015, significantly greater (p = 0.0003) than the change reported from Barouéli District, where incidence rates remained the same.

Conclusions: From 2012 to 2015, the annual IRS campaigns in Ségou are associated with several hundred thousand fewer cases of malaria. This work supports the growing evidence that shows that IRS with non-pyrethroid insecticides is a wise public health investment in areas with documented pyrethroid resistance, high rates of LLIN coverage, and where house structures and population densities are appropriate. Additionally, this work highlights the utility of quality-assured and validated routine surveillance and well defined observational analyses to rapidly assess the impact of malaria control interventions in operational settings, helping to empower evidence-based decision making and to further grow the evidence base needed to better understand when and where to utilize new vector control tools as they become available.
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http://dx.doi.org/10.1186/s12936-017-2168-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5761159PMC
January 2018

Malaria, malnutrition, and birthweight: A meta-analysis using individual participant data.

PLoS Med 2017 Aug 8;14(8):e1002373. Epub 2017 Aug 8.

Department of Pediatrics, Division of Neonatal-Perinatal Medicine, School of Medicine, UNC-Chapel Hill, Chapel Hill, North Carolina, United States of America.

Background: Four studies previously indicated that the effect of malaria infection during pregnancy on the risk of low birthweight (LBW; <2,500 g) may depend upon maternal nutritional status. We investigated this dependence further using a large, diverse study population.

Methods And Findings: We evaluated the interaction between maternal malaria infection and maternal anthropometric status on the risk of LBW using pooled data from 14,633 pregnancies from 13 studies (6 cohort studies and 7 randomized controlled trials) conducted in Africa and the Western Pacific from 1996-2015. Studies were identified by the Maternal Malaria and Malnutrition (M3) initiative using a convenience sampling approach and were eligible for pooling given adequate ethical approval and availability of essential variables. Study-specific adjusted effect estimates were calculated using inverse probability of treatment-weighted linear and log-binomial regression models and pooled using a random-effects model. The adjusted risk of delivering a baby with LBW was 8.8% among women with malaria infection at antenatal enrollment compared to 7.7% among uninfected women (adjusted risk ratio [aRR] 1.14 [95% confidence interval (CI): 0.91, 1.42]; N = 13,613), 10.5% among women with malaria infection at delivery compared to 7.9% among uninfected women (aRR 1.32 [95% CI: 1.08, 1.62]; N = 11,826), and 15.3% among women with low mid-upper arm circumference (MUAC <23 cm) at enrollment compared to 9.5% among women with MUAC ≥ 23 cm (aRR 1.60 [95% CI: 1.36, 1.87]; N = 9,008). The risk of delivering a baby with LBW was 17.8% among women with both malaria infection and low MUAC at enrollment compared to 8.4% among uninfected women with MUAC ≥ 23 cm (joint aRR 2.13 [95% CI: 1.21, 3.73]; N = 8,152). There was no evidence of synergism (i.e., excess risk due to interaction) between malaria infection and MUAC on the multiplicative (p = 0.5) or additive scale (p = 0.9). Results were similar using body mass index (BMI) as an anthropometric indicator of nutritional status. Meta-regression results indicated that there may be multiplicative interaction between malaria infection at enrollment and low MUAC within studies conducted in Africa; however, this finding was not consistent on the additive scale, when accounting for multiple comparisons, or when using other definitions of malaria and malnutrition. The major limitations of the study included availability of only 2 cross-sectional measurements of malaria and the limited availability of ultrasound-based pregnancy dating to assess impacts on preterm birth and fetal growth in all studies.

Conclusions: Pregnant women with malnutrition and malaria infection are at increased risk of LBW compared to women with only 1 risk factor or none, but malaria and malnutrition do not act synergistically.
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http://dx.doi.org/10.1371/journal.pmed.1002373DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5549702PMC
August 2017

Burden and impact of Plasmodium vivax in pregnancy: A multi-centre prospective observational study.

PLoS Negl Trop Dis 2017 Jun 12;11(6):e0005606. Epub 2017 Jun 12.

Barcelona Center for International Health Research, CRESIB, ISGlobal, Hospital Clínic - Universitat de Barcelona, Barcelona, Spain.

Background: Despite that over 90 million pregnancies are at risk of Plasmodium vivax infection annually, little is known about the epidemiology and impact of the infection in pregnancy.

Methodology And Principal Findings: We undertook a health facility-based prospective observational study in pregnant women from Guatemala (GT), Colombia (CO), Brazil (BR), India (IN) and Papua New Guinea PNG). Malaria and anemia were determined during pregnancy and fetal outcomes assessed at delivery. A total of 9388 women were enrolled at antennal care (ANC), of whom 53% (4957) were followed until delivery. Prevalence of P. vivax monoinfection in maternal blood at delivery was 0.4% (20/4461) by microscopy [GT 0.1%, CO 0.5%, BR 0.1%, IN 0.2%, PNG 1.2%] and 7% (104/1488) by PCR. P. falciparum monoinfection was found in 0.5% (22/4463) of women by microscopy [GT 0%, CO 0.5%, BR 0%, IN 0%, PNG 2%]. P. vivax infection was observed in 0.4% (14/3725) of placentas examined by microscopy and in 3.7% (19/508) by PCR. P. vivax in newborn blood was detected in 0.02% (1/4302) of samples examined by microscopy [in cord blood; 0.05% (2/4040) by microscopy, and 2.6% (13/497) by PCR]. Clinical P. vivax infection was associated with increased risk of maternal anemia (Odds Ratio-OR, 5.48, [95% CI 1.83-16.41]; p = 0.009), while submicroscopic vivax infection was not associated with increased risk of moderate-severe anemia (Hb<8g/dL) (OR, 1.16, [95% CI 0.52-2.59]; p = 0.717), or low birth weight (<2500g) (OR, 0.52, [95% CI, 0.23-1.16]; p = 0.110).

Conclusions: In this multicenter study, the prevalence of P. vivax infection in pregnancy by microscopy was overall low across all endemic study sites; however, molecular methods revealed a significant number of submicroscopic infections. Clinical vivax infection in pregnancy was associated with maternal anemia, which may be deleterious for infant's health. These results may help to guide maternal health programs in settings where vivax malaria is endemic; they also highlight the need of addressing a vulnerable population such as pregnant women while embracing malaria elimination in endemic countries.
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http://dx.doi.org/10.1371/journal.pntd.0005606DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5481034PMC
June 2017

Community-based intermittent mass testing and treatment for malaria in an area of high transmission intensity, western Kenya: study design and methodology for a cluster randomized controlled trial.

Malar J 2017 06 7;16(1):240. Epub 2017 Jun 7.

Division of Parasitic Diseases and Malaria, Center for Global Health, Centers for Disease Control and Prevention, Atlanta, GA, 30333, USA.

Most human Plasmodium infections in western Kenya are asymptomatic and are believed to contribute importantly to malaria transmission. Elimination of asymptomatic infections requires active treatment approaches, such as mass testing and treatment (MTaT) or mass drug administration (MDA), as infected persons do not seek care for their infection. Evaluations of community-based approaches that are designed to reduce malaria transmission require careful attention to study design to ensure that important effects can be measured accurately. This manuscript describes the study design and methodology of a cluster-randomized controlled trial to evaluate a MTaT approach for malaria transmission reduction in an area of high malaria transmission. Ten health facilities in western Kenya were purposively selected for inclusion. The communities within 3 km of each health facility were divided into three clusters of approximately equal population size. Two clusters around each health facility were randomly assigned to the control arm, and one to the intervention arm. Three times per year for 2 years, after the long and short rains, and again before the long rains, teams of community health volunteers visited every household within the intervention arm, tested all consenting individuals with malaria rapid diagnostic tests, and treated all positive individuals with an effective anti-malarial. The effect of mass testing and treatment on malaria transmission was measured through population-based longitudinal cohorts, outpatient visits for clinical malaria, periodic population-based cross-sectional surveys, and entomological indices.
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http://dx.doi.org/10.1186/s12936-017-1883-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5463392PMC
June 2017

Maternal Malaria and Malnutrition (M3) initiative, a pooled birth cohort of 13 pregnancy studies in Africa and the Western Pacific.

BMJ Open 2016 12 21;6(12):e012697. Epub 2016 Dec 21.

Department of Clinical Sciences, Liverpool School of Tropical Medicine, Liverpool, UK.

Purpose: The Maternal Malaria and Malnutrition (M3) initiative has pooled together 13 studies with the hope of improving understanding of malaria-nutrition interactions during pregnancy and to foster collaboration between nutritionists and malariologists.

Participants: Data were pooled on 14 635 singleton, live birth pregnancies from women who had participated in 1 of 13 pregnancy studies. The 13 studies cover 8 countries in Africa and Papua New Guinea in the Western Pacific conducted from 1996 to 2015.

Findings To Date: Data are available at the time of antenatal enrolment of women into their respective parent study and at delivery. The data set comprises essential data such as malaria infection status, anthropometric assessments of maternal nutritional status, presence of anaemia and birth weight, as well as additional variables such gestational age at delivery for a subset of women. Participating studies are described in detail with regard to setting and primary outcome measures, and summarised data are available from each contributing cohort.

Future Plans: This pooled birth cohort is the largest pregnancy data set to date to permit a more definite evaluation of the impact of plausible interactions between poor nutritional status and malaria infection in pregnant women on fetal growth and gestational length. Given the current comparative lack of large pregnancy cohorts in malaria-endemic settings, compilation of suitable pregnancy cohorts is likely to provide adequate statistical power to assess malaria-nutrition interactions, and could point towards settings where such interactions are most relevant. The M3 cohort may thus help to identify pregnant women at high risk of adverse outcomes who may benefit from tailored intensive antenatal care including nutritional supplements and alternative or intensified malaria prevention regimens, and the settings in which these interventions would be most effective.
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http://dx.doi.org/10.1136/bmjopen-2016-012697DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5223676PMC
December 2016

Intermittent Preventive Treatment with Sulfadoxine-Pyrimethamine: More Than Just an Antimalarial?

Am J Trop Med Hyg 2017 Jan 19;96(1):9-10. Epub 2016 Dec 19.

Malaria and Neglected Tropical Diseases, Center for Malaria Control and Elimination, PATH, Seattle, Washington.

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http://dx.doi.org/10.4269/ajtmh.16-0888DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5239716PMC
January 2017

Effectiveness of insecticide-treated bednets in malaria prevention in Haiti: a case-control study.

Lancet Glob Health 2017 01 26;5(1):e96-e103. Epub 2016 Nov 26.

Division of Parasitic Diseases and Malaria, US Centers for Disease Control and Prevention, Atlanta, GA, USA.

Background: Insecticide-treated bednets (ITNs) are effective in preventing malaria where vectors primarily bite indoors and late at night, but their effectiveness is uncertain where vectors bite outdoors and earlier in the evening. We studied the effectiveness of ITNs following a mass distribution in Haiti from May to September, 2012, where the Anopheles albimanus vector bites primarily outdoors and often when people are awake.

Methods: In this case-control study, we enrolled febrile patients presenting to outpatient departments at 17 health facilities throughout Haiti from Sept 4, 2012, to Feb 27, 2014, who were tested with malaria rapid diagnostic tests (RDTs), and administered questionnaires on ITN use and other risk factors. Cases were defined by positive RDT and controls were febrile patients from the same clinic with a negative RDT. Our primary analysis retrospectively matched cases and controls by age, sex, location, and date, and used conditional logistic regression on the matched sample. A sensitivity analysis used propensity scores to match patients on ITN use propensity and analyse malaria among ITN users and non-users. Additional ITN bioefficacy and entomological data were collected.

Findings: We enrolled 9317 patients, including 378 (4%) RDT-positive cases. 1202 (13%) patients reported ITN use. Post-hoc matching of cases and controls yielded 362 cases and 1201 matched controls, 19% (333) of whom reported consistent campaign net use. After using propensity scores to match on consistent campaign ITN use, 2298 patients, including 138 (7%) RDT-positive cases, were included: 1149 consistent campaign ITN users and 1149 non-consistent campaign ITN users. Both analyses revealed that ITNs did not significantly protect against clinical malaria (odds ratio [OR]=0·95, 95% CI 0·68-1·32, p=0·745 for case-control analysis; OR=0·95, 95% CI 0·45-1·97, p=0·884 for propensity score analysis). ITN and entomological data indicated good ITN physical integrity and bioefficacy, and no permethrin resistance among local mosquitoes.

Interpretation: We found no evidence that mass ITN campaigns reduce clinical malaria in this observational study in Haiti; alternative malaria control strategies should be prioritised.

Funding: The Global Fund to Fight AIDS, Tuberculosis, and Malaria, and the US-based Centers for Disease Control and Prevention (CDC).
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http://dx.doi.org/10.1016/S2214-109X(16)30238-8DOI Listing
January 2017

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

Malar J 2016 Sep 22;15(1):488. Epub 2016 Sep 22.

Malaria Elimination Initiative, Global Health Group, University of California, San Francisco, 550 16th Street, 3rd Floor, San Francisco, CA, USA.

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.
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http://dx.doi.org/10.1186/s12936-016-1518-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5034437PMC
September 2016

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

Malar J 2016 07 22;15(1):376. Epub 2016 Jul 22.

Division of Parasitic Diseases and Malaria, Center for Global Health, Centers for Disease Control and Prevention, Atlanta, GA, USA.

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.
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http://dx.doi.org/10.1186/s12936-016-1436-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4957415PMC
July 2016

Safety and immunogenicity of RTS,S/AS01 malaria vaccine in infants and children with WHO stage 1 or 2 HIV disease: a randomised, double-blind, controlled trial.

Lancet Infect Dis 2016 Oct 7;16(10):1134-1144. Epub 2016 Jul 7.

Division of Parasitic Diseases and Malaria, Centers for Global Health, Centers for Disease Control and Prevention, Atlanta, GA, USA.

Background: Malaria remains a major global public health concern, especially in sub-Saharan Africa. The RTS,S/AS01 malaria candidate vaccine was reviewed by the European Medicines Agency and received a positive scientific opinion; WHO subsequently recommended pilot implementation in sub-Saharan African countries. Because malaria and HIV overlap geographically, HIV-infected children should be considered for RTS,S/AS01 vaccination. We therefore aimed to assess the safety of RTS,S/AS01 in HIV-infected children at two sites in western Kenya.

Methods: We did a randomised, double-blind, controlled trial at the clinical trial sites of the Kenya Medical Research Institute (KEMRI)-Walter Reed Army Institute of research in Kisumu and the KEMRI/US Centers for Disease Control and Prevention in Siaya. Eligible participants were infants and children aged from 6 weeks to 17 months with WHO stage 1 or 2 HIV disease (documented positive by DNA PCR), whether or not they were receiving antiretroviral therapy (ART). We randomly assigned participants (1:1) to receive three doses of either RTS,S/AS01 or rabies vaccine (both 0·5 mL per dose by intramuscular injection), given once per month at 0, 1, and 2 months. We did the treatment allocation using a web-based central randomisation system stratified by age (6 weeks-4 months, 5-17 months), and by baseline CD4% (<10, 10-14, 15-19, and ≥20). Data were obtained in an observer-blind manner, and the vaccine recipient, their parent or carer, the funder, and investigators responsible for the assessment of endpoints were all masked to treatment allocation (only staff responsible for the preparation and administration of the vaccines were aware of the assignment and these individuals played no other role in the study). We provided ART, even if the participants were not receiving ART before the study, and daily co-trimoxazole for prevention of opportunistic infections. The primary outcome was the occurrence of serious adverse events until 14 months after dose 1 of the vaccine, assessed in the intention-to-treat population. This trial was registered at ClinicalTrials.gov, number NCT01148459.

Findings: Between July 30, 2010, and May 24, 2013, we enrolled 200 children to our study and randomly assigned 99 to receive RTS,S/AS01 and 101 to receive rabies vaccine. 177 (89%) of the 200 children enrolled completed 14 months of follow-up. Serious adverse events were noted in 41 (41·4%, 95% CI 31·6-51·8) of 99 RTS,S/AS01 recipients and 37 (36·6%, 27·3-46·8) of 101 rabies-vaccine recipients (relative risk 1·1, 95% CI 0·8-1·6). 20 (20·2%, 95% CI 12·8-29·5) of 99 RTS,S/AS01 recipients and 12 (11·9%, 6·3-19·8) of 101 rabies-vaccine recipients had at least one serious adverse event within 30 days after vaccination, mainly pneumonia, febrile convulsions, and salmonella sepsis. Five (5·1%, 95% CI 1·7-11·4) of 99 RTS,S/AS01 recipients and four (4·0%, 1·1-9·8) of 101 rabies-vaccine recipients died, but no deaths were deemed related to vaccination. Mortality was associated with five cases of pneumonia (1% RTS,S/AS01 recipients vs 3% rabies-vaccine recipients), five cases of gastroenteritis (3% RTS,S/AS01 recipients vs 2% rabies-vaccine recipients), five cases of malnutrition (2% RTS,S/AS01 recipients vs 3% rabies-vaccine recipients), one case of sepsis (1% rabies-vaccine recipients), one case of Haemophilus influenza meningitis (1% rabies-vaccine recipients), and one case of tuberculosis (1% RTS,S/AS01 recipients).

Interpretation: RTS, S/AS01 was well tolerated when given to children with WHO clinical stage 1 or 2 HIV disease along with high antiretroviral and co-trimoxazole use. Children with HIV disease could be included in future RTS,S/AS01 vaccination programmes.

Funding: GlaxoSmithKline Biologicals SA and PATH Malaria Vaccine Initiative.
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http://dx.doi.org/10.1016/S1473-3099(16)30161-XDOI Listing
October 2016
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