Implementation of a Randomized, Placebo-Controlled Trial of Live Attenuated Malaria Sporozoite Vaccines in an Indonesian Military Study Population.

Malaria eradication efforts prioritize safe and efficient vaccination strategies, although none with high-level efficacy against malaria infection are yet available. Among several vaccine candidates, Sanaria® PfSPZ Vaccine and Sanaria PfSPZ-CVac are, respectively, live radiation- and chemo-attenuated sporozoite vaccines designed to prevent infection with Plasmodium falciparum, the leading cause of malaria-related morbidity and mortality. We are conducting a randomized normal saline placebo-controlled trial called IDSPZV1 that will analyze the safety, tolerability, immunogenicity, and efficacy of PfSPZ Vaccine and PfSPZ-CVac administered pre-deployment to malaria-naive Indonesian soldiers assigned to temporary duties in a high malaria transmission area. We describe the manifold challenges of enrolling and immunizing 345 soldier participants at their home base in western Indonesia before their nearly 6,000-km voyage to eastern Indonesia, where they are being monitored for incident P. falciparum and Plasmodium vivax malaria cases during 9 months of exposure. The unique regulatory, ethical, and operational complexities of this trial demonstrate the importance of thorough planning, frequent communication, and close follow-up with stakeholders. Effective engagement with the military community and the ability to adapt to unanticipated events have proven key to the success of this trial.

Forest-goers as a heterogeneous population at high-risk for malaria: a case-control study in Aceh Province, Indonesia.

BACKGROUND: A major challenge to malaria elimination is identifying and targeting populations that are harbouring residual infections and contributing to persistent transmission. In many near-elimination settings in Southeast Asia, it is known that forest-goers are at higher risk for malaria infection, but detailed information on their behaviours and exposures is not available. METHODS: In Aceh Province, Indonesia, a near-elimination setting where a growing proportion of malaria is due to Plasmodium knowlesi, a case-control study was conducted to identify risk factors for symptomatic malaria, characteristics of forest-goers, and key intervention points. From April 2017 to September 2018, cases and controls were recruited and enrolled in a 1:3 ratio. Cases had confirmed malaria infection by rapid diagnostic test or microscopy detected at a health facility (HF). Gender-matched controls were recruited from passive case detection among individuals with suspected malaria who tested negative at a health facility (HF controls), and community-matched controls were recruited among those testing negative during active case detection. Multivariable logistic regression (unconditional for HF controls and conditional for community controls) was used to identify risk factors for symptomatic malaria infection. RESULTS: There were 45 cases, of which 27 were P. knowlesi, 17 were Plasmodium vivax, and one was not determined. For controls, 509 and 599 participants were recruited from health facilities and the community, respectively. Forest exposures were associated with high odds of malaria; in particular, working and sleeping in the forest (HF controls: adjusted odds ratio (aOR) 21.66, 95% CI 5.09-92.26; community controls: aOR 16.78, 95% CI 2.19-128.7) and having a second residence in the forest (aOR 6.29, 95% CI 2.29-17.31 and 13.53, 95% CI 2.10-87.12). Male forest-goers were a diverse population employed in a variety of occupations including logging, farming, and mining, sleeping in settings, such as huts, tents, and barracks, and working in a wide range of group sizes. Reported use of protective measures, such as nets, hammock nets, mosquito coils, and repellents was low among forest-goers and interventions at forest residences were absent. CONCLUSIONS: Second residences in the forest and gaps in use of protective measures point to key malaria interventions to improve coverage in forest-going populations at risk for P. knowlesi and P. vivax in Aceh, Indonesia. Intensified strategies tailored to specific sub-populations will be essential to achieve elimination.

Impact of the COVID-19 pandemic on tuberculosis control in Indonesia: a nationwide longitudinal analysis of programme data.

BACKGROUND: The impact of the COVID-19 pandemic on tuberculosis control in high-burden countries has not been adequately assessed. We aimed to estimate the impact of the COVID-19 pandemic on the national tuberculosis programme in Indonesia, in association with indicators of human development and health-system capacity across all 514 districts in 34 provinces. METHODS: We did a nationwide longitudinal analysis to compare tuberculosis case notification, treatment coverage, and mortality rates in Indonesia before (2016-19) and during (2020-21) the COVID-19 pandemic. The following outcomes were assessed: the district-level quarterly reported tuberculosis case notification rate (number of all reported tuberculosis cases per 100 000 population), treatment coverage (proportion of tuberculosis patients who started treatment), and all-cause mortality rate in patients with tuberculosis (number of reported deaths per 100 000 population). District-level data on COVID-19 incidence and deaths, health-system capacity, and human development and sociodemographics were also analysed. Multilevel linear spline regression was done to assess quarterly time trends for the three outcomes. FINDINGS: During the COVID-19 pandemic, the tuberculosis case notification rate declined by 26% (case notification rate ratio 0·74, 95% CI 0·72-0·77) and treatment coverage declined by 11% (treatment coverage ratio 0·89, 95% CI 0·88-0·90), but there was no significant increase in all-cause mortality (all-cause mortality rate ratio 0·97, 95% CI 0·91-1·04) compared with the pre-pandemic period. In the second year of the pandemic, we observed a partial recovery of the case notification rate from Q1 to Q4 of 2021, a persistent decrease in treatment coverage, and a decrease in the all-cause mortality rate from Q2 of 2020 to Q4 of 2021. The multivariable analysis showed that the reduction in the tuberculosis case notification rate was associated with a higher COVID-19 incidence rate (adjusted odds ratio 3·1, 95% CI 1·1-8·6, for the highest compared with the lowest group) and fewer GeneXpert machines for tuberculosis diagnosis (3·1, 1·0-9·4, for the lowest compared with the highest group) per 100 000 population. The reduction in tuberculosis treatment coverage was associated with higher COVID-19 incidence (adjusted odds ratio 11·7, 95% CI 1·5-93·4, for the highest compared with the lowest group), fewer primary health centres (10·6, 4·1-28·0, for the lowest compared with the middle-high group), and a very low number of doctors (0·3, 0·1-0·9, for the low-middle compared with the lowest group) per 100 000 population. No factors were shown to be significantly associated with all-cause mortality. INTERPRETATION: The COVID-19 pandemic adversely and unevenly affected the national tuberculosis programme across Indonesia, with the greatest impacts observed in districts with the lowest health-system capacity. These disruptions could lead to an escalation in tuberculosis transmission in the coming years, warranting the need for intensified efforts to control tuberculosis and strengthen local health systems. FUNDING: Wellcome Africa Asia Programme Vietnam. TRANSLATION: For the Bahasa translation of the abstract see Supplementary Materials section.

Clinical characteristics and factors associated with COVID-19-related mortality and hospital admission during the first two epidemic waves in 5 rural provinces in Indonesia: A retrospective cohort study.

BACKGROUND: Data on coronavirus disease 2019 (COVID-19) clinical characteristics and severity from resource-limited settings are limited. This study examined clinical characteristics and factors associated with COVID-19 mortality and hospitalisation in rural settings of Indonesia, from 1 January to 31 July, 2021. METHODS: This retrospective cohort included individuals diagnosed with COVID-19 based on polymerase chain reaction or rapid antigen diagnostic test, from five rural provinces in Indonesia. We extracted demographic and clinical data, including hospitalisation and mortality from a new piloted COVID-19 information system named Sistem Informasi Surveilans Epidemiologi (SISUGI). We used mixed-effect logistic regression to examine factors associated with COVID-19-related mortality and hospitalisation. RESULTS: Of 6,583 confirmed cases, 205 (3.1%) died and 1,727 (26.2%) were hospitalised. The median age was 37 years (Interquartile range 26-51), with 825 (12.6%) under 20 years, and 3,371 (51.2%) females. Most cases were symptomatic (4,533; 68.9%); 319 (4.9%) had a clinical diagnosis of pneumonia and 945 (14.3%) presented with at least one pre-existing comorbidity. Age-specific mortality rates were 0.9% (2/215) for 0-4 years; 0% (0/112) for 5-9 years; 0% (1/498) for 10-19 years; 0.8% (11/1,385) for 20-29 years; 0.9% (12/1,382) for 30-39 years; 2.1% (23/1,095) for 40-49 years; 5.4% (57/1,064) for 50-59 years; 10.8% (62/576) for 60-69 years; 15.9% (37/232) for ≥70 years. Older age, pre-existing diabetes, chronic kidney disease, liver diseases, malignancy, and pneumonia were associated with higher risk of mortality and hospitalisation. Pre-existing hypertension, cardiac diseases, COPD, and immunocompromised condition were associated with risk of hospitalisation but not with mortality. There was no association between province-level density of healthcare workers with mortality and hospitalisation. CONCLUSION: The risk of COVID-19-related mortality and hospitalisation was associated with higher age, pre-existing chronic comorbidities, and clinical pneumonia. The findings highlight the need for prioritising enhanced context-specific public health action to reduce mortality and hospitalisation risk among older and comorbid rural populations.

Geographical variations and district-level factors associated with COVID-19 mortality in Indonesia: a nationwide ecological study.

BACKGROUND: Ensuring health equity, especially for vulnerable populations in less developed settings with poor health system is essential for the current and future global health threats. This study examined geographical variations of COVID-19 mortality and its association with population health characteristics, health care capacity in responding pandemic, and socio-economic characteristics across 514 districts in Indonesia. METHODS: This nationwide ecological study included aggregated data of COVID-19 cases and deaths from all 514 districts in Indonesia, recorded in the National COVID-19 Task Force database, during the first two years of the epidemic, from 1 March 2020 to 27 February 2022. The dependent variable was district-level COVID-19 mortality rate per 100,000 populations. The independent variables include district-level COVID-19 incidence rate, population health, health care capacity, and socio-demographics data from government official sources. We used multivariable ordinal logistic regression to examine factors associated with higher mortality rate. RESULTS: Of total 5,539,333 reported COVID-19 cases, 148,034 (2.7%) died, and 5,391,299 (97.4%) were recovered. The district-level mortality rate ranged from 0 to 284 deaths per 100,000 populations. The top five districts with the highest mortality rate were Balikpapan (284 deaths per 100,000 populations), Semarang (263), Madiun (254), Magelang (250), and Yogyakarta (247). A higher COVID-19 incidence (coefficient 1.64, 95% CI 1.22 to 1.75), a higher proportion of ≥ 60 years old population (coefficient 0.26, 95% CI 0.06 to 0.46), a higher prevalence of diabetes mellitus (coefficient 0.60, 95% CI 0.37 to 0.84), a lower prevalence of obesity (coefficient -0.32, 95% CI -0.56 to -0.08), a lower number of nurses per population (coefficient -0.27, 95% CI -0.50 to -0.04), a higher number of midwives per population (coefficient 0.32, 95% CI 0.13 to 0.50), and a higher expenditure (coefficient 0.34, 95% CI 0.10 to 0.57) was associated with a higher COVID-19 mortality rate. CONCLUSION: COVID-19 mortality rate in Indonesia was highly heterogeneous and associated with higher COVID-19 incidence, different prevalence of pre-existing comorbidity, healthcare capacity in responding the pandemic, and socio-economic characteristics. This study revealed the need of controlling both COVID-19 and those known comorbidities, health capacity strengthening, and better resource allocation to ensure optimal health outcomes for vulnerable population.

Pandemic inequity in a megacity: a multilevel analysis of individual, community and healthcare vulnerability risks for COVID-19 mortality in Jakarta, Indonesia.

INTRODUCTION: Worldwide, the 33 recognised megacities comprise approximately 7% of the global population, yet account for 20% COVID-19 deaths. The specific inequities and other factors within megacities that affect vulnerability to COVID-19 mortality remain poorly defined. We assessed individual, community-level and healthcare factors associated with COVID-19-related mortality in a megacity of Jakarta, Indonesia, during two epidemic waves spanning 2 March 2020 to 31 August 2021. METHODS: This retrospective cohort included residents of Jakarta, Indonesia, with PCR-confirmed COVID-19. We extracted demographic, clinical, outcome (recovered or died), vaccine coverage data and disease prevalence from Jakarta Health Office surveillance records, and collected subdistrict level sociodemographics data from various official sources. We used multilevel logistic regression to examine individual, community and subdistrict-level healthcare factors and their associations with COVID-19 mortality. RESULTS: Of 705 503 cases with a definitive outcome by 31 August 2021, 694 706 (98.5%) recovered and 10 797 (1.5%) died. The median age was 36 years (IQR 24-50), 13.2% (93 459) were <18 years and 51.6% were female. The subdistrict level accounted for 1.5% of variance in mortality (p<0.0001). Mortality ranged from 0.9 to 1.8% by subdistrict. Individual-level factors associated with death were older age, male sex, comorbidities and age <5 years during the first wave (adjusted OR (aOR)) 1.56, 95% CI 1.04 to 2.35; reference: age 20-29 years). Community-level factors associated with death were poverty (aOR for the poorer quarter 1.35, 95% CI 1.17 to 1.55; reference: wealthiest quarter) and high population density (aOR for the highest density 1.34, 95% CI 1.14 to 2.58; reference: the lowest). Healthcare factor associated with death was low vaccine coverage (aOR for the lowest coverage 1.25, 95% CI 1.13 to 1.38; reference: the highest). CONCLUSION: In addition to individual risk factors, living in areas with high poverty and density, and low healthcare performance further increase the vulnerability of communities to COVID-19-associated death in urban low-resource settings.

Quantifying spatial heterogeneity of malaria in the endemic Papua region of Indonesia: Analysis of epidemiological surveillance data.

Background: As control efforts progress towards elimination, malaria is likely to become more spatially concentrated in few local areas. The purpose of this study was to quantify and characterise spatial heterogeneity in malaria transmission-intensity across highly endemic Indonesian Papua. Methods: We analysed individual-level malaria surveillance data for nearly half a million cases (2019-2020) reported in the Papua and West Papua provinces and adapted the Gini index approach to quantify spatial heterogeneity at the district and health-unit levels. In this context, high Gini index implies disproportionately distributed malaria cases across the region. We showed malaria incidence trends and the spatial and temporal distribution of sociodemographic characteristics and aetiological parasites among cases. Findings: While Papua province accounted for the majority of malaria cases reported in the region and had seen a rise in transmission since 2015, West Papua province had maintained a comparatively low incidence. We observed that Gini index estimates were high, particularly when the lower spatial scale of health units was evaluated. The Gini index appears to be inversely associated to annual parasite-incidence, as well as the proportions of vivax malaria, male sex, and adults. Interpretation: This study suggests that areas with varying levels of transmission-intensities exhibited distinct characteristics. Malaria was distributed in a markedly disproportionate manner throughout the region, emphasising the need for spatially targeted interventions. Periodic quantification and characterisation of risk heterogeneity at various spatial levels using routine malaria surveillance data may aid in tracking progress towards elimination and guiding evidence-informed prioritisation of resource allocation. Funding: The study was funded by the Australian Government Department of Foreign Affairs and Trade Indo-Pacific Centre for Health Security through the Strengthening Preparedness in the Asia-Pacific Region through Knowledge (SPARK) project.

Mortality among healthcare workers in Indonesia during 18 months of COVID-19.

The impact of SARS-CoV-2 infections upon Indonesian health care workers (HCWs) is unknown due to the lack of systematic collection and analysis of mortality data specific to HCWs in this setting. This report details the results of a systematic compilation, abstraction and analysis of HCW fatalities in Indonesia during the first 18 months of COVID-19. HCW who passed away between March 2020 and July 2021 were identified using Pusara Digital, a community-based digital cemetery database dedicated to HCW. We calculated the mortality rates and death risk ratio of HCWs versus the general population. The analysis indicates that at least 1,545 HCWs died during the study period. Death rates among males and females HCWs were nearly equivalent (51% vs. 49%). The majority were physicians and specialists (535, 35%), nurses (428, 28%), and midwives (359, 23%). Most deaths occurred between the ages of 40 to 59 years old, with the median age being 50 years (IQR: 39-59). At least 322 deaths (21%) occurred with pre-existing conditions, including 45 pregnant women. During the first 18 months of COVID-19 in Indonesia, we estimated a minimum HCW mortality rate of 1.707 deaths per 1,000 HCWs. The provincial rates of HCW mortality ranged from 0.136 (West Sulawesi) to 5.32 HCW deaths per 1,000 HCWs (East Java). The HCW mortality rate was significantly higher than that of the general population (RR = 4.92, 95% CI 4.67-5.17). The COVID-19 pandemic in Indonesia resulted in the loss of many hundreds of HCWs, the majority of whom were senior healthcare workers. The HCW mortality rate is five times that of the general population. A national systematic surveillance of occupational mortality is urgently needed in this setting.

Sub-national disparities in accessing anti-malarial drug treatment in eastern Indonesia.

BACKGROUND: Poor access to health care providers was among the contributing factors to less prompt and ineffective malaria treatment. This limitation could cause severe diseases in remote areas. This study examined the sub-national disparities and predictors in accessing anti-malarial drug treatment among adults in Eastern Indonesia. METHODS: The study analyzed a subset of the 2018 National Basic Health Survey conducted in all 34 provinces in Indonesia. We extracted socio-demographic data of 4655 adult respondents diagnosed with malaria in the past 12 months in five provinces in Eastern Indonesia. The association between socio-demographic factors and the access to anti-malarial drug treatment was assessed using logistic regression. RESULTS: Over 20% of respondents diagnosed with malaria within last 12 months admitted that they did not receive anti-malarial drug treatment (range 12-29.9%). The proportion of untreated cases was 12.0% in East Nusa Tenggara, 29.9% in Maluku, 23.1% in North Maluku, 12.7% in West Papua, and 15.6% in Papua. The likelihood of receiving anti-malarial drug treatment was statistically lower in Maluku (adjusted OR = 0.258; 95% CI 0.161-0.143) and North Maluku (adjusted OR = 0.473; 95% CI 0.266-0.840) than those in Eastern Nusa Tenggara (reference). Urban respondents were less likely to receive malaria treatment than rural (adjusted OR = 0.545; 95% CI 0.431-0.689). CONCLUSIONS: This study found that there were sub-national disparities in accessing anti-malarial drug treatment in Eastern Indonesia, with a high proportion of untreated malaria cases across the areas. Findings from this study could be used as baseline information to improve access to anti-malarial drug treatment and better target malaria intervention in Eastern Indonesia.

Using syndromic measures of mortality to capture the dynamics of COVID-19 in Java, Indonesia, in the context of vaccination rollout.

BACKGROUND: As in many countries, quantifying COVID-19 spread in Indonesia remains challenging due to testing limitations. In Java, non-pharmaceutical interventions (NPIs) were implemented throughout 2020. However, as a vaccination campaign launches, cases and deaths are rising across the island. METHODS: We used modelling to explore the extent to which data on burials in Jakarta using strict COVID-19 protocols (C19P) provide additional insight into the transmissibility of the disease, epidemic trajectory, and the impact of NPIs. We assess how implementation of NPIs in early 2021 will shape the epidemic during the period of likely vaccine rollout. RESULTS: C19P burial data in Jakarta suggest a death toll approximately 3.3 times higher than reported. Transmission estimates using these data suggest earlier, larger, and more sustained impact of NPIs. Measures to reduce sub-national spread, particularly during Ramadan, substantially mitigated spread to more vulnerable rural areas. Given current trajectory, daily cases and deaths are likely to increase in most regions as the vaccine is rolled out. Transmission may peak in early 2021 in Jakarta if current levels of control are maintained. However, relaxation of control measures is likely to lead to a subsequent resurgence in the absence of an effective vaccination campaign. CONCLUSIONS: Syndromic measures of mortality provide a more complete picture of COVID-19 severity upon which to base decision-making. The high potential impact of the vaccine in Java is attributable to reductions in transmission to date and dependent on these being maintained. Increases in control in the relatively short-term will likely yield large, synergistic increases in vaccine impact.

Defining malaria risks among forest workers in Aceh, Indonesia: a formative assessment.

BACKGROUND: Following a dramatic decline of malaria cases in Aceh province, geographically-based reactive case detection (RACD) was recently evaluated as a tool to improve surveillance with the goal of malaria elimination. While RACD detected few cases in households surrounding index cases, engaging in forest work was identified as a risk factor for malaria and infections from Plasmodium knowlesi-a non-human primate malaria parasite-were more common than expected. This qualitative formative assessment was conducted to improve understanding of malaria risk from forest work and identify strategies for targeted surveillance among forest workers, including adapting reactive case detection. METHODS: Between June and August, 2016, five focus groups and 18 in-depth interviews with forest workers and key informants were conducted in each of four subdistricts in Aceh Besar and Aceh Jaya districts. Themes included: types of forest activities, mobility of workers, interactions with non-human primates, malaria prevention and treatment-seeking behaviours, and willingness to participate in malaria surveys at forest work sites and using peer-referral. RESULTS: Reported forest activities included mining, logging, and agriculture in the deep forest and along the forest fringe. Forest workers, particularly miners and loggers, described often spending weeks to months at work sites in makeshift housing, rarely utilizing mosquito prevention and, upon fever, self-medicating and seeking care from traditional healers or pharmacies rather than health facilities. Non-human primates are frequently observed near work sites, and most forest work locations are within a day's journey of health clinics. Employers and workers expressed interest in undertaking malaria testing and in participating in survey recruitment by peer-referral and at work sites. CONCLUSIONS: Diverse groups of forest workers in Aceh are potentially exposed to malaria through forest work. Passive surveillance and household-based screening may under-estimate malaria burden due to extended stays in the forest and health-seeking behaviours. Adapting active surveillance to specifically target forest workers through work-site screening and/or peer-referral appears promising for addressing currently undetected infections.

Estimating the burden of dengue and the impact of release of wMel Wolbachia-infected mosquitoes in Indonesia: a modelling study.

BACKGROUND: Wolbachia-infected mosquitoes reduce dengue virus transmission, and city-wide releases in Yogyakarta city, Indonesia, are showing promising entomological results. Accurate estimates of the burden of dengue, its spatial distribution and the potential impact of Wolbachia are critical in guiding funder and government decisions on its future wider use. METHODS: Here, we combine multiple modelling methods for burden estimation to predict national case burden disaggregated by severity and map the distribution of burden across the country using three separate data sources. An ensemble of transmission models then predicts the estimated reduction in dengue transmission following a nationwide roll-out of wMel Wolbachia. RESULTS: We estimate that 7.8 million (95% uncertainty interval [UI] 1.8-17.7 million) symptomatic dengue cases occurred in Indonesia in 2015 and were associated with 332,865 (UI 94,175-754,203) lost disability-adjusted life years (DALYs). The majority of dengue's burden was due to non-severe cases that did not seek treatment or were challenging to diagnose in outpatient settings leading to substantial underreporting. Estimated burden was highly concentrated in a small number of large cities with 90% of dengue cases occurring in 15.3% of land area. Implementing a nationwide Wolbachia population replacement programme was estimated to avert 86.2% (UI 36.2-99.9%) of cases over a long-term average. CONCLUSIONS: These results suggest interventions targeted to the highest burden cities can have a disproportionate impact on dengue burden. Area-wide interventions, such as Wolbachia, that are deployed based on the area covered could protect people more efficiently than individual-based interventions, such as vaccines, in such dense environments.

Negligible Impact of Mass Screening and Treatment on Mesoendemic Malaria Transmission at West Timor in Eastern Indonesia: A Cluster-Randomized Trial.

Background: Mass screening and treatment (MST) aims to reduce malaria risk in communities by identifying and treating infected persons without regard to illness. Methods: A cluster-randomized trial evaluated malaria incidence with and without MST. Clusters were randomized to 3, 2, or no MST interventions: MST3, 6 clusters (156 households/670 individuals); MST2, 5 clusters (89 households/423 individuals); and MST0, 5 clusters (174 households/777 individuals). All clusters completed the study with 14 residents withdrawing. In a cohort of 324 schoolchildren (MST3, n = 124; MST2, n = 57; MST0, n = 143) negative by microscopy at enrollment, we evaluated the incidence density of malaria during 3 months of MST and 3 months following. The MST intervention involved community-wide expert malaria microscopic screening and standard therapy with dihydroartemisinin-piperaquine and primaquine for glucose-6 phosphate dehydrogenase-normal subjects. All blood examinations included polymerase chain reaction assays, which did not guide on-site treatment. Results: The risk ratios for incidence density of microscopically patent malaria in MST3 or MST2 relative to that in MST0 clusters were 1.00 (95% confidence interval [CI], .53-1.91) and 1.22 (95% CI, .42-3.55), respectively. Similar results were obtained with molecular analysis and species-specific (P. falciparum and P. vivax) infections. Microscopically subpatent, untreated infections accounted for 72% of those infected. Conclusions: Two or 3 rounds of MST within 3 months did not impact the force of anopheline mosquito-borne infection in these communities. The high rate of untreated microscopically subpatent infections likely explains the observed poor impact. Clinical Trials Registration: NCT01878357.

Estimating Geographical Variation in the Risk of Zoonotic Plasmodium knowlesi Infection in Countries Eliminating Malaria.

BACKGROUND: Infection by the simian malaria parasite, Plasmodium knowlesi, can lead to severe and fatal disease in humans, and is the most common cause of malaria in parts of Malaysia. Despite being a serious public health concern, the geographical distribution of P. knowlesi malaria risk is poorly understood because the parasite is often misidentified as one of the human malarias. Human cases have been confirmed in at least nine Southeast Asian countries, many of which are making progress towards eliminating the human malarias. Understanding the geographical distribution of P. knowlesi is important for identifying areas where malaria transmission will continue after the human malarias have been eliminated. METHODOLOGY/PRINCIPAL FINDINGS: A total of 439 records of P. knowlesi infections in humans, macaque reservoir and vector species were collated. To predict spatial variation in disease risk, a model was fitted using records from countries where the infection data coverage is high. Predictions were then made throughout Southeast Asia, including regions where infection data are sparse. The resulting map predicts areas of high risk for P. knowlesi infection in a number of countries that are forecast to be malaria-free by 2025 (Malaysia, Cambodia, Thailand and Vietnam) as well as countries projected to be eliminating malaria (Myanmar, Laos, Indonesia and the Philippines). CONCLUSIONS/SIGNIFICANCE: We have produced the first map of P. knowlesi malaria risk, at a fine-scale resolution, to identify priority areas for surveillance based on regions with sparse data and high estimated risk. Our map provides an initial evidence base to better understand the spatial distribution of this disease and its potential wider contribution to malaria incidence. Considering malaria elimination goals, areas for prioritised surveillance are identified.

Predicting the geographical distributions of the macaque hosts and mosquito vectors of Plasmodium knowlesi malaria in forested and non-forested areas.

BACKGROUND: Plasmodium knowlesi is a zoonotic pathogen, transmitted among macaques and to humans by anopheline mosquitoes. Information on P. knowlesi malaria is lacking in most regions so the first step to understand the geographical distribution of disease risk is to define the distributions of the reservoir and vector species. METHODS: We used macaque and mosquito species presence data, background data that captured sampling bias in the presence data, a boosted regression tree model and environmental datasets, including annual data for land classes, to predict the distributions of each vector and host species. We then compared the predicted distribution of each species with cover of each land class. RESULTS: Fine-scale distribution maps were generated for three macaque host species (Macaca fascicularis, M. nemestrina and M. leonina) and two mosquito vector complexes (the Dirus Complex and the Leucosphyrus Complex). The Leucosphyrus Complex was predicted to occur in areas with disturbed, but not intact, forest cover (> 60% tree cover) whereas the Dirus Complex was predicted to occur in areas with 10-100% tree cover as well as vegetation mosaics and cropland. Of the macaque species, M. nemestrina was mainly predicted to occur in forested areas whereas M. fascicularis was predicted to occur in vegetation mosaics, cropland, wetland and urban areas in addition to forested areas. CONCLUSIONS: The predicted M. fascicularis distribution encompassed a wide range of habitats where humans are found. This is of most significance in the northern part of its range where members of the Dirus Complex are the main P. knowlesi vectors because these mosquitoes were also predicted to occur in a wider range of habitats. Our results support the hypothesis that conversion of intact forest into disturbed forest (for example plantations or timber concessions), or the creation of vegetation mosaics, will increase the probability that members of the Leucosphyrus Complex occur at these locations, as well as bringing humans into these areas. An explicit analysis of disease risk itself using infection data is required to explore this further. The species distributions generated here can now be included in future analyses of P. knowlesi infection risk.

Global database of matched Plasmodium falciparum and P. vivax incidence and prevalence records from 1985-2013.

Measures of clinical incidence are necessary to help estimate the burden of a disease. Incidence is a metric not commonly measured in malariology because the longitudinal surveys required are costly and labour intensive. This database is an effort to collate published incidence records obtained using active case detection for Plasmodium falciparum and Plasmodium vivax malaria. The literature search methods, data abstraction procedures and data processing procedures are described here. A total of 1,680 spatio-temporally unique incidence records were collected for the database: 1,187 for P. falciparum and 493 for P. vivax. These data were gathered to model the relationship between clinical incidence and prevalence of infection and can be used for a variety of modelling exercises including the assessment of change in disease burden in relation to age and control interventions. The subset of data that have been used for such modelling exercises are described and identified.

The global distribution of the arbovirus vectors Aedes aegypti and Ae. albopictus.

Dengue and chikungunya are increasing global public health concerns due to their rapid geographical spread and increasing disease burden. Knowledge of the contemporary distribution of their shared vectors, Aedes aegypti and Aedes albopictus remains incomplete and is complicated by an ongoing range expansion fuelled by increased global trade and travel. Mapping the global distribution of these vectors and the geographical determinants of their ranges is essential for public health planning. Here we compile the largest contemporary database for both species and pair it with relevant environmental variables predicting their global distribution. We show Aedes distributions to be the widest ever recorded; now extensive in all continents, including North America and Europe. These maps will help define the spatial limits of current autochthonous transmission of dengue and chikungunya viruses. It is only with this kind of rigorous entomological baseline that we can hope to project future health impacts of these viruses.

The global compendium of Aedes aegypti and Ae. albopictus occurrence.

Aedes aegypti and Ae. albopictus are the main vectors transmitting dengue and chikungunya viruses. Despite being pathogens of global public health importance, knowledge of their vectors' global distribution remains patchy and sparse. A global geographic database of known occurrences of Ae. aegypti and Ae. albopictus between 1960 and 2014 was compiled. Herein we present the database, which comprises occurrence data linked to point or polygon locations, derived from peer-reviewed literature and unpublished studies including national entomological surveys and expert networks. We describe all data collection processes, as well as geo-positioning methods, database management and quality-control procedures. This is the first comprehensive global database of Ae. aegypti and Ae. albopictus occurrence, consisting of 19,930 and 22,137 geo-positioned occurrence records respectively. Both datasets can be used for a variety of mapping and spatial analyses of the vectors and, by inference, the diseases they transmit.

A comprehensive assessment of the malaria microscopy system of Aceh, Indonesia, in preparation for malaria elimination.

BACKGROUND: The Health Office of Aceh aims to eliminate malaria from Aceh Province, Indonesia by 2015. Malaria was formerly common in Aceh (population 4.5 million), but has declined dramatically in recent years consequent to post-tsunami control efforts. Successful elimination will depend upon rapid and accurate diagnosis and case follow-up at community level. A prerequisite to this is widespread coverage of high quality malaria diagnosis. This study describes the results of a comprehensive assessment of the malaria diagnostic capacity in Aceh as the province moves towards malaria elimination. METHODS: The study was conducted in 23 districts in Aceh from October 2010 to July 2011. Six types of questionnaires were used to collect data on competency of microscopists and laboratory capacity. Standardized slides were used to evaluate the proficiency of all microscopists. In addition, site visits to 17 primary health centres (PHC) assessed diagnostic practice and logistics capacity. RESULTS: Five hundred and seventy four malaria microscopists have been officially registered and assigned to duty in the 23 districts in Aceh Province. They work in 345 laboratories, predominantly in PHCs (69 %) and hospitals (25 %). Three laboratories were evaluated as adequate for all 30 elements, while 29 laboratories were adequate for less than five of 30 elements. Standardized proficiency tests showed that 413 microscopists were at basic (in training) level, with 10 advanced and 9 reference level. No microscopist achieved expert level. Neither the province nor any of Aceh's districts has a standardized inventory and logistics database for malaria diagnostics, nor did any of the surveyed laboratories operate a quality assurance programme for either microscopy or rapid diagnostic tests. CONCLUSIONS: The study highlights the importance of careful assessment of diagnostic capacity when embarking upon a large-scale malaria elimination programme. Aceh's laboratories have minimal infrastructure with nearly all microscopists still in training. On the positive side, a large workforce of microscopists has been assigned to laboratories with the needed equipment. Aceh will need to embark on a large-scale comprehensive quality assurance scheme if it is to achieve malaria elimination.

Defining the relationship between Plasmodium vivax parasite rate and clinical disease.

BACKGROUND: Though essential to the development and evaluation of national malaria control programmes, precise enumeration of the clinical illness burden of malaria in endemic countries remains challenging where local surveillance systems are incomplete. Strategies to infer annual incidence rates from parasite prevalence survey compilations have proven effective in the specific case of Plasmodium falciparum, but have yet to be developed for Plasmodium vivax. Moreover, defining the relationship between P. vivax prevalence and clinical incidence may also allow levels of endemicity to be inferred for areas where the information balance is reversed, that is, incident case numbers are more widely gathered than parasite surveys; both applications ultimately facilitating cartographic estimates of P. vivax transmission intensity and its ensuring disease burden. METHODS: A search for active case detection surveys was conducted and the recorded incidence values were matched to local, contemporary parasite rate measures and classified to geographic zones of differing relapse phenotypes. A hierarchical Bayesian model was fitted to these data to quantify the relationship between prevalence and incidence while accounting for variation among relapse zones. RESULTS: The model, fitted with 176 concurrently measured P. vivax incidence and prevalence records, was a linear regression of the logarithm of incidence against the logarithm of age-standardized prevalence. Specific relationships for the six relapse zones where data were available were drawn, as well as a pooled overall relationship. The slope of the curves varied among relapse zones; zones with short predicted time to relapse had steeper slopes than those observed to contain long-latency relapse phenotypes. CONCLUSIONS: The fitted relationships, along with appropriate uncertainty metrics, allow for estimates of clinical incidence of known confidence to be made from wherever P. vivax prevalence data are available. This is a prerequisite for cartographic-based inferences about the global burden of morbidity due to P. vivax, which will be used to inform control efforts.