Displaying publications 1 - 20 of 26 in total

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  1. Stark DJ, Fornace KM, Brock PM, Abidin TR, Gilhooly L, Jalius C, et al.
    Ecohealth, 2019 12;16(4):638-646.
    PMID: 30927165 DOI: 10.1007/s10393-019-01403-9
    Land-use changes can impact infectious disease transmission by increasing spatial overlap between people and wildlife disease reservoirs. In Malaysian Borneo, increases in human infections by the zoonotic malaria Plasmodium knowlesi are hypothesised to be due to increasing contact between people and macaques due to deforestation. To explore how macaque responses to environmental change impact disease risks, we analysed movement of a GPS-collared long-tailed macaque in a knowlesi-endemic area in Sabah, Malaysia, during a deforestation event. Land-cover maps were derived from satellite-based and aerial remote sensing data and models of macaque occurrence were developed to evaluate how macaque habitat use was influenced by land-use change. During deforestation, changes were observed in macaque troop home range size, movement speeds and use of different habitat types. Results of models were consistent with the hypothesis that macaque ranging behaviour is disturbed by deforestation events but begins to equilibrate after seeking and occupying a new habitat, potentially impacting human disease risks. Further research is required to explore how these changes in macaque movement affect knowlesi epidemiology on a wider spatial scale.
  2. Moyes CL, Henry AJ, Golding N, Huang Z, Singh B, Baird JK, et al.
    PLoS Negl Trop Dis, 2014 Mar;8(3):e2780.
    PMID: 24676231 DOI: 10.1371/journal.pntd.0002780
    BACKGROUND: The simian malaria parasite, Plasmodium knowlesi, can cause severe and fatal disease in humans yet it is rarely included in routine public health reporting systems for malaria and its geographical range is largely unknown. Because malaria caused by P. knowlesi is a truly neglected tropical disease, there are substantial obstacles to defining the geographical extent and risk of this disease. Information is required on the occurrence of human cases in different locations, on which non-human primates host this parasite and on which vectors are able to transmit it to humans. We undertook a systematic review and ranked the existing evidence, at a subnational spatial scale, to investigate the potential geographical range of the parasite reservoir capable of infecting humans.

    METHODOLOGY/PRINCIPAL FINDINGS: After reviewing the published literature we identified potential host and vector species and ranked these based on how informative they are for the presence of an infectious parasite reservoir, based on current evidence. We collated spatial data on parasite occurrence and the ranges of the identified host and vector species. The ranked spatial data allowed us to assign an evidence score to 475 subnational areas in 19 countries and we present the results on a map of the Southeast and South Asia region.

    CONCLUSIONS/SIGNIFICANCE: We have ranked subnational areas within the potential disease range according to evidence for presence of a disease risk to humans, providing geographical evidence to support decisions on prevention, management and prophylaxis. This work also highlights the unknown risk status of large parts of the region. Within this unknown category, our map identifies which areas have most evidence for the potential to support an infectious reservoir and are therefore a priority for further investigation. Furthermore we identify geographical areas where further investigation of putative host and vector species would be highly informative for the region-wide assessment.

  3. Manin BO, Drakeley CJ, Chua TH
    PLoS One, 2018;13(8):e0202905.
    PMID: 30138386 DOI: 10.1371/journal.pone.0202905
    Anopheles balabacensis, the primary vector of Plasmodium knowlesi in Sabah, Malaysia, is both zoophilic and anthropophilic, feeding on macaques as well as humans. It is the dominant Anopheles species found in Kudat Division where it is responsible for all the cases of P. knowlesi. However there is a paucity of basic biological and ecological information on this vector. We investigated the genetic variation of this species using the sequences of cox1 (1,383 bp) and cox2 (685 bp) to gain an insight into the population genetics and inter-population gene flow in Sabah. A total of 71 An. balabacensis were collected from seven districts constituting 14 subpopulations. A total of 17, 10 and 25 haplotypes were detected in the subpopulations respectively using the cox1, cox2 and the combined sequence. Some of the haplotypes were common among the subpopulations due to gene flow occurring between them. AMOVA showed that the genetic variation was high within subpopulations as compared to between subpopulations. Mantel test results showed that the variation between subpopulations was not due to the geographical distance between them. Furthermore, Tajima's D and Fu's Fs tests showed that An. balabacensis in Sabah is experiencing population expansion and growth. High gene flow between the subpopulations was indicated by the low genetic distance and high gene diversity in the cox1, cox2 and the combined sequence. However the population at Lipasu Lama appeared to be isolated possibly due to its higher altitude at 873 m above sea level.
  4. Imai N, White MT, Ghani AC, Drakeley CJ
    PLoS Negl Trop Dis, 2014 Jul;8(7):e2978.
    PMID: 25058400 DOI: 10.1371/journal.pntd.0002978
    INTRODUCTION: Plasmodium knowlesi is now recognised as a leading cause of malaria in Malaysia. As humans come into increasing contact with the reservoir host (long-tailed macaques) as a consequence of deforestation, assessing the potential for a shift from zoonotic to sustained P. knowlesi transmission between humans is critical.

    METHODS: A multi-host, multi-site transmission model was developed, taking into account the three areas (forest, farm, and village) where transmission is thought to occur. Latin hypercube sampling of model parameters was used to identify parameter sets consistent with possible prevalence in macaques and humans inferred from observed data. We then explore the consequences of increasing human-macaque contact in the farm, the likely impact of rapid treatment, and the use of long-lasting insecticide-treated nets (LLINs) in preventing wider spread of this emerging infection.

    RESULTS: Identified model parameters were consistent with transmission being sustained by the macaques with spill over infections into the human population and with high overall basic reproduction numbers (up to 2267). The extent to which macaques forage in the farms had a non-linear relationship with human infection prevalence, the highest prevalence occurring when macaques forage in the farms but return frequently to the forest where they experience higher contact with vectors and hence sustain transmission. Only one of 1,046 parameter sets was consistent with sustained human-to-human transmission in the absence of macaques, although with a low human reproduction number (R(0H) = 1.04). Simulations showed LLINs and rapid treatment provide personal protection to humans with maximal estimated reductions in human prevalence of 42% and 95%, respectively.

    CONCLUSION: This model simulates conditions where P. knowlesi transmission may occur and the potential impact of control measures. Predictions suggest that conventional control measures are sufficient at reducing the risk of infection in humans, but they must be actively implemented if P. knowlesi is to be controlled.

  5. Herman LS, Fornace K, Phelan J, Grigg MJ, Anstey NM, William T, et al.
    PLoS Negl Trop Dis, 2018 Jun;12(6):e0006457.
    PMID: 29902183 DOI: 10.1371/journal.pntd.0006457
    BACKGROUND: Plasmodium knowlesi is the most common cause of malaria in Malaysian Borneo, with reporting limited to clinical cases presenting to health facilities and scarce data on the true extent of transmission. Serological estimations of transmission have been used with other malaria species to garner information about epidemiological patterns. However, there are a distinct lack of suitable serosurveillance tools for this neglected disease.

    METHODOLOGY/PRINCIPAL FINDINGS: Using in silico tools, we designed and expressed four novel P. knowlesi protein products to address the distinct lack of suitable serosurveillance tools: PkSERA3 antigens 1 and 2, PkSSP2/TRAP and PkTSERA2 antigen 1. Antibody prevalence to these antigens was determined by ELISA for three time-points post-treatment from a hospital-based clinical treatment trial in Sabah, East Malaysia (n = 97 individuals; 241 total samples for all time points). Higher responses were observed for the PkSERA3 antigen 2 (67%, 65/97) across all time-points (day 0: 36.9% 34/92; day 7: 63.8% 46/72; day 28: 58.4% 45/77) with significant differences between the clinical cases and controls (n = 55, mean plus 3 SD) (day 0 p<0.0001; day 7 p<0.0001; day 28 p<0.0001). Using boosted regression trees, we developed models to classify P. knowlesi exposure (cross-validated AUC 88.9%; IQR 86.1-91.3%) and identified the most predictive antibody responses.

    CONCLUSIONS/SIGNIFICANCE: The PkSERA3 antigen 2 had the highest relative variable importance in all models. Further validation of these antigens is underway to determine the specificity of these tools in the context of multi-species infections at the population level.

  6. Grignard L, Shah S, Chua TH, William T, Drakeley CJ, Fornace KM
    J Infect Dis, 2019 11 06;220(12):1946-1949.
    PMID: 31418017 DOI: 10.1093/infdis/jiz397
    To determine the presence and species composition of malaria infections, we screened a subset of samples collected during a cross-sectional survey in Northern Sabah, Malaysia using highly sensitive molecular techniques. Results identified 54 asymptomatic submicroscopic malaria infections, including a large cluster of Plasmodium falciparum and 3 P. knowlesi infections. We additionally identified 2 monoinfections with the zoonotic malaria Plasmodium cynomolgi, both in individuals reporting no history of forest activities or contact with macaques. Results highlight the need for improved surveillance strategies to detect these infections and determine public health impacts.
  7. Grigg MJ, William T, Drakeley CJ, Jelip J, von Seidlein L, Barber BE, et al.
    BMJ Open, 2014 Aug 22;4(8):e006004.
    PMID: 25149186 DOI: 10.1136/bmjopen-2014-006004
    INTRODUCTION: Plasmodium knowlesi has long been present in Malaysia, and is now an emerging cause of zoonotic human malaria. Cases have been confirmed throughout South-East Asia where the ranges of its natural macaque hosts and Anopheles leucosphyrus group vectors overlap. The majority of cases are from Eastern Malaysia, with increasing total public health notifications despite a concurrent reduction in Plasmodium falciparum and P. vivax malaria. The public health implications are concerning given P. knowlesi has the highest risk of severe and fatal disease of all Plasmodium spp in Malaysia. Current patterns of risk and disease vary based on vector type and competence, with individual exposure risks related to forest and forest-edge activities still poorly defined. Clustering of cases has not yet been systematically evaluated despite reports of peri-domestic transmission and known vector competence for human-to-human transmission.

    METHODS AND ANALYSIS: A population-based case-control study will be conducted over a 2-year period at two adjacent districts in north-west Sabah, Malaysia. Confirmed malaria cases presenting to the district hospital sites meeting relevant inclusion criteria will be requested to enrol. Three community controls matched to the same village as the case will be selected randomly. Study procedures will include blood sampling and administration of household and individual questionnaires to evaluate potential exposure risks associated with acquisition of P. knowlesi malaria. Secondary outcomes will include differences in exposure variables between P. knowlesi and other Plasmodium spp, risk of severe P. knowlesi malaria, and evaluation of P. knowlesi case clustering. Primary analysis will be per protocol, with adjusted ORs for exposure risks between cases and controls calculated using conditional multiple logistic regression models.

    ETHICS: This study has been approved by the human research ethics committees of Malaysia, the Menzies School of Health Research, Australia, and the London School of Hygiene and Tropical Medicine, UK.

  8. Grigg MJ, Barber BE, Marfurt J, Imwong M, William T, Bird E, et al.
    PLoS One, 2016;11(3):e0149519.
    PMID: 26930493 DOI: 10.1371/journal.pone.0149519
    BACKGROUND: Malaria caused by zoonotic Plasmodium knowlesi is an emerging threat in Eastern Malaysia. Despite demonstrated vector competency, it is unknown whether human-to-human (H-H) transmission is occurring naturally. We sought evidence of drug selection pressure from the antimalarial sulfadoxine-pyrimethamine (SP) as a potential marker of H-H transmission.

    METHODS: The P. knowlesi dihdyrofolate-reductase (pkdhfr) gene was sequenced from 449 P. knowlesi malaria cases from Sabah (Malaysian Borneo) and genotypes evaluated for association with clinical and epidemiological factors. Homology modelling using the pvdhfr template was used to assess the effect of pkdhfr mutations on the pyrimethamine binding pocket.

    RESULTS: Fourteen non-synonymous mutations were detected, with the most common being at codon T91P (10.2%) and R34L (10.0%), resulting in 21 different genotypes, including the wild-type, 14 single mutants, and six double mutants. One third of the P. knowlesi infections were with pkdhfr mutants; 145 (32%) patients had single mutants and 14 (3%) had double-mutants. In contrast, among the 47 P. falciparum isolates sequenced, three pfdhfr genotypes were found, with the double mutant 108N+59R being fixed and the triple mutants 108N+59R+51I and 108N+59R+164L occurring with frequencies of 4% and 8%, respectively. Two non-random spatio-temporal clusters were identified with pkdhfr genotypes. There was no association between pkdhfr mutations and hyperparasitaemia or malaria severity, both hypothesized to be indicators of H-H transmission. The orthologous loci associated with resistance in P. falciparum were not mutated in pkdhfr. Subsequent homology modelling of pkdhfr revealed gene loci 13, 53, 120, and 173 as being critical for pyrimethamine binding, however, there were no mutations at these sites among the 449 P. knowlesi isolates.

    CONCLUSION: Although moderate diversity was observed in pkdhfr in Sabah, there was no evidence this reflected selective antifolate drug pressure in humans.

  9. Grigg MJ, William T, Barber BE, Rajahram GS, Menon J, Schimann E, et al.
    Clin Infect Dis, 2018 07 18;67(3):350-359.
    PMID: 29873683 DOI: 10.1093/cid/ciy065
    Background: Plasmodium knowlesi is increasingly reported in Southeast Asia, but prospective studies of its clinical spectrum in children and comparison with autochthonous human-only Plasmodium species are lacking.

    Methods: Over 3.5 years, we prospectively assessed patients of any age with molecularly-confirmed Plasmodium monoinfection presenting to 3 district hospitals in Sabah, Malaysia.

    Results: Of 481 knowlesi, 172 vivax, and 96 falciparum malaria cases enrolled, 44 (9%), 71 (41%), and 31 (32%) children aged ≤12 years. Median parasitemia was lower in knowlesi malaria (2480/μL [interquartile range, 538-8481/μL]) than in falciparum (9600/μL; P < .001) and vivax malaria. In P. knowlesi, World Health Organization-defined anemia was present in 82% (95% confidence interval [CI], 67%-92%) of children vs 36% (95% CI, 31%-41%) of adults. Severe knowlesi malaria occurred in 6.4% (95% CI, 3.9%-8.3%) of adults but not in children; the commenst severity criterion was acute kideny injury. No patient had coma. Age, parasitemia, schizont proportion, abdominal pain, and dyspnea were independently associated with severe knowlesi malaria, with parasitemia >15000/μL the best predictor (adjusted odds ratio, 16.1; negative predictive value, 98.5%; P < .001). Two knowlesi-related adult deaths occurred (fatality rate: 4.2/1000 adults).

    Conclusions: Age distribution and parasitemia differed markedly in knowlesi malaria compared to human-only species, with both uncomplicated and severe disease occurring at low parasitemia. Severe knowlesi malaria occurred only in adults; however, anemia was more common in children despite lower parasitemia. Parasitemia independently predicted knowlesi disease severity: Intravenous artesunate is warranted initially for those with parasitemia >15000/μL.

  10. Grigg MJ, Cox J, William T, Jelip J, Fornace KM, Brock PM, et al.
    Lancet Planet Health, 2017 Jun 09;1(3):e97-e104.
    PMID: 28758162 DOI: 10.1016/S2542-5196(17)30031-1
    BACKGROUND: The emergence of human malaria due to the monkey parasite Plasmodium knowlesi threatens elimination efforts in southeast Asia. Changes in land use are thought to be driving the rise in reported P knowlesi cases, but the role of individual-level factors is unclear. To address this knowledge gap we assessed human and environmental factors associated with zoonotic knowlesi malaria risk.

    METHODS: We did this population-based case-control study over a 2 year period in the state of Sabah in Malaysia. We enrolled cases with microscopy-positive, PCR-confirmed malaria who presented to two primary referral hospitals serving the adjacent districts of Kudat and Kota Marudu. We randomly selected three malaria-negative community controls per case, who were matched by village within 2 weeks of case detection. We obtained questionnaire data on demographics, behaviour, and residential malaria risk factors, and we also assessed glucose-6-phosphate dehydrogenase (G6PD) enzyme activity. We used conditional logistic regression models to evaluate exposure risk between P knowlesi cases and controls, and between P knowlesi and human-only Plasmodium spp malaria cases.

    FINDINGS: From Dec 5, 2012, to Jan 30, 2015, we screened 414 patients and subsequently enrolled 229 cases with P knowlesi malaria mono-infection and 91 cases with other Plasmodium spp infection. We enrolled 953 matched controls, including 683 matched to P knowlesi cases and 270 matched to non-P knowlesi cases. Age 15 years or older (adjusted odds ratio [aOR] 4·16, 95% CI 2·09-8·29, p<0·0001), male gender (4·20, 2·54-6·97, p<0·0001), plantation work (3·50, CI, 1·34-9·15, p=0·011), sleeping outside (3·61, 1·48-8·85, p=0·0049), travel (2·48, 1·45-4·23, p=0·0010), being aware of the presence of monkeys in the past 4 weeks (3·35, 1·91-5·88, p<0·0001), and having open eaves or gaps in walls (2·18, 1·33-3·59, p=0·0021) were independently associated with increased risk of symptomatic P knowlesi infection. Farming occupation (aOR 1·89, 95% CI 1·07-3·35, p=0·028), clearing vegetation (1·89, 1·11-3·22, p=0·020), and having long grass around the house (2·08, 1·25-3·46, p=0·0048) increased risk for P knowlesi infection but not other Plasmodium spp infection. G6PD deficiency seemed to be protective against P knowlesi (aOR 0·20, 95% CI 0·04-0·96, p=0·045), as did residual insecticide spraying of household walls (0·52, 0·31-0·87, p=0·014), with the presence of young sparse forest (0·35, 0·20-0·63, p=00040) and rice paddy around the house (0·16, 0·03-0·78, 0·023) also associated with decreased risk.

    INTERPRETATION: Adult men working in agricultural areas were at highest risk of knowlesi malaria, although peri-domestic transmission also occurrs. Human behavioural factors associated with P knowlesi transmission could be targeted in future public health interventions.

    FUNDING: United Kingdom Medical Research Council, Natural Environment Research Council, Economic and Social Research Council, and Biotechnology and Biosciences Research Council.

  11. Grigg MJ, Lubis IN, Tetteh KKA, Barber BE, William T, Rajahram GS, et al.
    Adv Parasitol, 2021;113:77-130.
    PMID: 34620386 DOI: 10.1016/bs.apar.2021.08.002
    Within the overlapping geographical ranges of P. knowlesi monkey hosts and vectors in Southeast Asia, an estimated 1.5 billion people are considered at risk of infection. P. knowlesi can cause severe disease and death, the latter associated with delayed treatment occurring from misdiagnosis. Although microscopy is a sufficiently sensitive first-line tool for P. knowlesi detection for most low-level symptomatic infections, misdiagnosis as other Plasmodium species is common, and the majority of asymptomatic infections remain undetected. Current point-of-care rapid diagnostic tests demonstrate insufficient sensitivity and poor specificity for differentiating P. knowlesi from other Plasmodium species. Molecular tools including nested, real-time, and single-step PCR, and loop-mediated isothermal amplification (LAMP), are sensitive for P. knowlesi detection. However, higher cost and inability to provide the timely point-of-care diagnosis needed to guide appropriate clinical management has limited their routine use in most endemic clinical settings. P. knowlesi is likely underdiagnosed across the region, and improved diagnostic and surveillance tools are required. Reference laboratory molecular testing of malaria cases for both zoonotic and non-zoonotic Plasmodium species needs to be more widely implemented by National Malaria Control Programs across Southeast Asia to accurately identify the burden of zoonotic malaria and more precisely monitor the success of human-only malaria elimination programs. The implementation of specific serological tools for P. knowlesi would assist in determining the prevalence and distribution of asymptomatic and submicroscopic infections, the absence of transmission in certain areas, and associations with underlying land use change for future spatially targeted interventions.
  12. Fornace KM, Drakeley CJ, William T, Espino F, Cox J
    Trends Parasitol, 2014 Nov;30(11):514-9.
    PMID: 25443854 DOI: 10.1016/j.pt.2014.09.001
    The potential applications of unmanned aerial vehicles (UAVs), or drones, have generated intense interest across many fields. UAVs offer the potential to collect detailed spatial information in real time at relatively low cost and are being used increasingly in conservation and ecological research. Within infectious disease epidemiology and public health research, UAVs can provide spatially and temporally accurate data critical to understanding the linkages between disease transmission and environmental factors. Using UAVs avoids many of the limitations associated with satellite data (e.g., long repeat times, cloud contamination, low spatial resolution). However, the practicalities of using UAVs for field research limit their use to specific applications and settings. UAVs fill a niche but do not replace existing remote-sensing methods.
  13. Fornace KM, Brock PM, Abidin TR, Grignard L, Herman LS, Chua TH, et al.
    Lancet Planet Health, 2019 04;3(4):e179-e186.
    PMID: 31029229 DOI: 10.1016/S2542-5196(19)30045-2
    BACKGROUND: Land use changes disrupt ecosystems, altering the transmission of vector-borne diseases. These changes have been associated with increasing incidence of zoonotic malaria caused by Plasmodium knowlesi; however, the population-level distributions of infection and exposure remain unknown. We aimed to measure prevalence of serological exposure to P knowlesi and assess associated risk factors.

    METHODS: We did an environmentally stratified, population-based, cross-sectional survey across households in the Kudat, Kota Marudu, Pitas, and Ranau districts in northern Sabah, Malaysia, encompassing a range of ecologies. Using blood samples, the transmission intensity of P knowlesi and other malaria species was measured by specific antibody prevalence and infection detected using molecular methods. Proportions and configurations of land types were extracted from maps derived from satellite images; a data-mining approach was used to select variables. A Bayesian hierarchical model for P knowlesi seropositivity was developed, incorporating questionnaire data about individual and household-level risk factors with selected landscape factors.

    FINDINGS: Between Sept 17, 2015, and Dec 12, 2015, 10 100 individuals with a median age of 25 years (range 3 months to 105 years) were sampled from 2849 households in 180 villages. 5·1% (95% CI 4·8-5·4) were seropositive for P knowlesi, and marked historical decreases were observed in the transmission of Plasmodium falciparum and Plasmodium vivax. Nine Plasmodium spp infections were detected. Age, male sex, contact with macaques, forest use, and raised house construction were positively associated with P knowlesi exposure, whereas residing at higher geographical elevations and use of insecticide were protective. Agricultural and forest variables, such as proportions and fragmentation of land cover types, predicted exposure at different spatial scales from households.

    INTERPRETATION: Although few infections were detected, P knowlesi exposure was observed in all demographic groups and was associated with occupational factors. Results suggest that agricultural expansion and forest fragmentation affect P knowlesi exposure, supporting linkages between land use change and P knowlesi transmission.

    FUNDING: UK Medical Research Council, Natural Environment Research Council, Economic and Social Research Council, and Biotechnology and Biosciences Research Council.

  14. Fornace KM, Surendra H, Abidin TR, Reyes R, Macalinao MLM, Stresman G, et al.
    Int J Health Geogr, 2018 06 18;17(1):21.
    PMID: 29914506 DOI: 10.1186/s12942-018-0141-0
    BACKGROUND: Identifying fine-scale spatial patterns of disease is essential for effective disease control and elimination programmes. In low resource areas without formal addresses, novel strategies are needed to locate residences of individuals attending health facilities in order to efficiently map disease patterns. We aimed to assess the use of Android tablet-based applications containing high resolution maps to geolocate individual residences, whilst comparing the functionality, usability and cost of three software packages designed to collect spatial information.

    RESULTS: Using Open Data Kit GeoODK, we designed and piloted an electronic questionnaire for rolling cross sectional surveys of health facility attendees as part of a malaria elimination campaign in two predominantly rural sites in the Rizal, Palawan, the Philippines and Kulon Progo Regency, Yogyakarta, Indonesia. The majority of health workers were able to use the tablets effectively, including locating participant households on electronic maps. For all households sampled (n = 603), health facility workers were able to retrospectively find the participant household using the Global Positioning System (GPS) coordinates and data collected by tablet computers. Median distance between actual house locations and points collected on the tablet was 116 m (IQR 42-368) in Rizal and 493 m (IQR 258-886) in Kulon Progo Regency. Accuracy varied between health facilities and decreased in less populated areas with fewer prominent landmarks.

    CONCLUSIONS: Results demonstrate the utility of this approach to develop real-time high-resolution maps of disease in resource-poor environments. This method provides an attractive approach for quickly obtaining spatial information on individuals presenting at health facilities in resource poor areas where formal addresses are unavailable and internet connectivity is limited. Further research is needed on how to integrate these with other health data management systems and implement in a wider operational context.

  15. Fornace KM, Nuin NA, Betson M, Grigg MJ, William T, Anstey NM, et al.
    J Infect Dis, 2016 Mar 01;213(5):784-7.
    PMID: 26433222 DOI: 10.1093/infdis/jiv475
    Although asymptomatic carriage of human malaria species has been widely reported, the extent of asymptomatic, submicroscopic Plasmodium knowlesi parasitemia is unknown. In this study, samples were obtained from individuals residing in households or villages of symptomatic malaria cases with the aim of detecting submicroscopic P. knowlesi in this population. Four published molecular assays were used to confirm the presence of P. knowlesi. Latent class analysis revealed that the estimated proportion of asymptomatic individuals was 6.9% (95% confidence interval, 5.6%-8.4%). This study confirms the presence of a substantial number of asymptomatic monoinfections across all age groups; further work is needed to estimate prevalence in the wider community.
  16. Fornace KM, Abidin TR, Alexander N, Brock P, Grigg MJ, Murphy A, et al.
    Emerg Infect Dis, 2016 Feb;22(2):201-8.
    PMID: 26812373 DOI: 10.3201/eid2202.150656
    The zoonotic malaria species Plasmodium knowlesi has become the main cause of human malaria in Malaysian Borneo. Deforestation and associated environmental and population changes have been hypothesized as main drivers of this apparent emergence. We gathered village-level data for P. knowlesi incidence for the districts of Kudat and Kota Marudu in Sabah state, Malaysia, for 2008-2012. We adjusted malaria records from routine reporting systems to reflect the diagnostic uncertainty of microscopy for P. knowlesi. We also developed negative binomial spatial autoregressive models to assess potential associations between P. knowlesi incidence and environmental variables derived from satellite-based remote-sensing data. Marked spatial heterogeneity in P. knowlesi incidence was observed, and village-level numbers of P. knowlesi cases were positively associated with forest cover and historical forest loss in surrounding areas. These results suggest the likelihood that deforestation and associated environmental changes are key drivers in P. knowlesi transmission in these areas.
  17. Fornace KM, Herman LS, Abidin TR, Chua TH, Daim S, Lorenzo PJ, et al.
    PLoS Negl Trop Dis, 2018 Jun;12(6):e0006432.
    PMID: 29902171 DOI: 10.1371/journal.pntd.0006432
    BACKGROUND: Primarily impacting poor, rural populations, the zoonotic malaria Plasmodium knowlesi is now the main cause of human malaria within Malaysian Borneo. While data is increasingly available on symptomatic cases, little is known about community-level patterns of exposure and infection. Understanding the true burden of disease and associated risk factors within endemic communities is critical for informing evidence-based control measures.

    METHODOLOGY/PRINCIPAL FINDINGS: We conducted comprehensive surveys in three areas where P. knowlesi transmission is reported: Limbuak, Pulau Banggi and Matunggung, Kudat, Sabah, Malaysia and Bacungan, Palawan, the Philippines. Infection prevalence was low with parasites detected by PCR in only 0.2% (4/2503) of the population. P. knowlesi PkSERA3 ag1 antibody responses were detected in 7.1% (95% CI: 6.2-8.2%) of the population, compared with 16.1% (14.6-17.7%) and 12.6% (11.2-14.1%) for P. falciparum and P. vivax. Sero-prevalence was low in individuals <10 years old for P. falciparum and P. vivax consistent with decreased transmission of non-zoonotic malaria species. Results indicated marked heterogeneity in transmission intensity between sites and P. knowlesi exposure was associated with agricultural work (OR 1.63; 95% CI 1.07-2.48) and higher levels of forest cover (OR 2.40; 95% CI 1.29-4.46) and clearing (OR 2.14; 95% CI 1.35-3.40) around houses. Spatial patterns of P. knowlesi exposure differed from exposure to non-zoonotic malaria and P. knowlesi exposed individuals were younger on average than individuals exposed to non-zoonotic malaria.

    CONCLUSIONS/SIGNIFICANCE: This is the first study to describe serological exposure to P. knowlesi and associated risk factors within endemic communities. Results indicate community-level patterns of infection and exposure differ markedly from demographics of reported cases, with higher levels of exposure among women and children. Further work is needed to understand these variations in risk across a wider population and spatial scale.

  18. Fornace KM, Drakeley CJ, Lindblade KA, Jelip J, Ahmed K
    Nat Commun, 2023 Sep 16;14(1):5750.
    PMID: 37717079 DOI: 10.1038/s41467-023-41546-6
    Increasing numbers of human zoonotic malaria cases are reported globally. Current malaria control measures cannot eliminate transmission from wildlife reservoirs, leaving many countries with no pathway to malaria elimination certification. New policies are needed to redefine elimination goals and certification.
  19. Diez Benavente E, Florez de Sessions P, Moon RW, Holder AA, Blackman MJ, Roper C, et al.
    PLoS Genet, 2017 Sep;13(9):e1007008.
    PMID: 28922357 DOI: 10.1371/journal.pgen.1007008
    The macaque parasite Plasmodium knowlesi is a significant concern in Malaysia where cases of human infection are increasing. Parasites infecting humans originate from genetically distinct subpopulations associated with the long-tailed (Macaca fascicularis (Mf)) or pig-tailed macaques (Macaca nemestrina (Mn)). We used a new high-quality reference genome to re-evaluate previously described subpopulations among human and macaque isolates from Malaysian-Borneo and Peninsular-Malaysia. Nuclear genomes were dimorphic, as expected, but new evidence of chromosomal-segment exchanges between subpopulations was found. A large segment on chromosome 8 originating from the Mn subpopulation and containing genes encoding proteins expressed in mosquito-borne parasite stages, was found in Mf genotypes. By contrast, non-recombining organelle genomes partitioned into 3 deeply branched lineages, unlinked with nuclear genomic dimorphism. Subpopulations which diverged in isolation have re-connected, possibly due to deforestation and disruption of wild macaque habitats. The resulting genomic mosaics reveal traits selected by host-vector-parasite interactions in a setting of ecological transition.
  20. Cuenca PR, Key S, Jumail A, Surendra H, Ferguson HM, Drakeley CJ, et al.
    Adv Parasitol, 2021;113:225-286.
    PMID: 34620384 DOI: 10.1016/bs.apar.2021.08.006
    Within the past two decades, incidence of human cases of the zoonotic malaria Plasmodium knowlesi has increased markedly. P. knowlesi is now the most common cause of human malaria in Malaysia and threatens to undermine malaria control programmes across Southeast Asia. The emergence of zoonotic malaria corresponds to a period of rapid deforestation within this region. These environmental changes impact the distribution and behaviour of the simian hosts, mosquito vector species and human populations, creating new opportunities for P. knowlesi transmission. Here, we review how landscape changes can drive zoonotic disease emergence, examine the extent and causes of these changes across Southeast and identify how these mechanisms may be impacting P. knowlesi dynamics. We review the current spatial epidemiology of reported P. knowlesi infections in people and assess how these demographic and environmental changes may lead to changes in transmission patterns. Finally, we identify opportunities to improve P. knowlesi surveillance and develop targeted ecological interventions within these landscapes.
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