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The emergence and spread of chloroquine-resistant Plasmodium vivax have necessitated the assessment of alternative blood schizonticidal drugs. In Vietnam, chloroquine-resistant P. vivax malaria has been reported. In an open-label, single-arm trial, the safety, tolerability, and efficacy of pyronaridine-artesunate (Pyramax, PA) was evaluated in Dak Nong province, Vietnam. A 3-day course of PA was administered to adults and children (≥20 kg) infected with P. vivax. Patients also received primaquine (0.25 mg/kg daily for 14 days). PA was well tolerated with transient asymptomatic increases in liver transaminases. The per-protocol proportion of patients with day 42 PCR-unadjusted adequate clinical and parasitological response was 96.0% (95% CI, 84.9%-99.0%, n = 48/50). The median parasite clearance time was 12 h (range, 12-36 h), with a median fever clearance time of 24 h (range, 12-60 h). Single nucleotide polymorphisms (SNPs) as potential genetic markers of reduced drug susceptibility were analyzed in three putative drug resistance markers, Pvcrt-o, Pvmdr1, and PvK12. Insertion at position K10 of the Pvcrt-o gene was found in 74.6% (44/59) of isolates. Pvmdr1 SNPs at Y976F and F1076L were present in 61% (36/59) and 78% (46/59), respectively. Amplification of Pvmdr1 gene (two copies) was found in 5.1% (3/59) of parasite samples. Only 5.1% (3/59) of isolates had mutation 552I of the PvK12 gene. Overall, PA rapidly cleared P. vivax blood asexual stages and was highly efficacious in treating vivax malaria, with no evidence of artemisinin resistance found. PA provides an alternative to chloroquine treatment for vivax malaria in Vietnam. CLINICAL TRIALS: This study is registered with the Australian New Zealand Clinical Trials Registry as ACTRN12618001429246.
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BACKGROUND: Malaria rapid diagnostic tests (RDTs) remain the main point-of-care tests for diagnosis of symptomatic Plasmodium falciparum malaria in endemic areas. However, parasites with gene deletions in the most common RDT target, histidine rich protein 2 (pfhrp2/HRP2), can produce false-negative RDT results leading to inadequate case management. The objective of this study was to determine the prevalence of hrp2/3 deletions causing false-negative RDT results in Vietnam (Gia Lai and Dak Lak provinces). METHODS: Individuals presenting with malaria symptoms at health facilities were screened for P. falciparum infection using light microscopy and HRP2-RDT (SD Bioline Malaria Antigen Pf/Pv RDT, Abbott). Microscopically confirmed P. falciparum infections were analysed for parasite species by 18S rRNA qPCR, and pfhrp2 and pfhrp3 exon2 deletions were investigated by nested PCR. pfhrp2 amplicons were sequenced by the Sanger method and HRP2 plasma levels were determined by enzyme-linked immunosorbent assay (ELISA). RESULTS: The prevalence of false-negative RDT results among symptomatic cases was 5.6% (15/270). No pfhrp2 and pfhrp3 deletions were identified. False-negative RDT results were associated with lower parasite density (p = 0.005) and lower HRP2 plasma concentrations (p < 0.001), as compared to positive RDT. CONCLUSIONS: The absence of hrp2/3 deletions detected in this survey suggests that HRP2-based malaria RDTs remain effective for the diagnosis of symptomatic P. falciparum malaria in Central Vietnam.
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Malaria Falciparum , Plasmodium falciparum , Humanos , Plasmodium falciparum/genética , Plasmodium falciparum/metabolismo , Proteínas Protozoarias/genética , Proteínas Protozoarias/metabolismo , Eliminación de Gen , Vietnam/epidemiología , Pruebas Diagnósticas de Rutina/métodos , Malaria Falciparum/diagnóstico , Malaria Falciparum/epidemiología , Malaria Falciparum/genética , Antígenos de Protozoos/genética , Antígenos de Protozoos/metabolismo , Reacción en Cadena en Tiempo Real de la PolimerasaRESUMEN
BACKGROUND: Malaria elimination by 2030 is an aim of many countries in the Greater Mekong Sub-region, including Vietnam. However, to achieve this goal and accelerate towards malaria elimination, countries need to determine the extent and prevalence of asymptomatic malaria as a potential reservoir for malaria transmission and the intensity of malaria transmission. The purpose of this study was to determine the prevalence of asymptomatic malaria and seropositivity rate in several districts of Gia Lai province in the Central Highlands of Vietnam. METHODS: A cross-sectional survey of asymptomatic malaria and serological testing was conducted in 3283 people living at 14 communes across seven districts in Gia Lai province in December 2016 to January 2017. Finger prick capillary blood samples were tested for malaria using rapid diagnostic testing and polymerase chain reaction (PCR), as well as detecting antibodies against 3 Plasmodium falciparum and 4 Plasmodium vivax antigens by indirect enzyme-linked immunosorbent assay (ELISA). Age-seroprevalence curves were fitted using reverse catalytic models with maximum likelihood. RESULTS: The study population was predominantly male (65.9%, 2165/3283), adults (88.7%, 2911/3283) and of a minority ethnicity (72.2%, 2371/3283), with most participants being farmers and outdoor government workers (90.2%, 2960/3283). Using a small volume of blood (≈ 10 µL) the PCR assay revealed that 1.74% (57/3283) of the participants had asymptomatic malaria (P. falciparum 1.07%, P. vivax 0.40%, Plasmodium malariae 0.15% and mixed infections 0.12%). In contrast, the annual malaria prevalence rates for clinical malaria in the communities where the participants lived were 0.12% (108/90,395) in 2016 and 0.22% (201/93,184) in 2017. Seropositivity for at least one P. falciparum or one P. vivax antigen was 38.5% (1257/3262) and 31.1% (1022/3282), respectively. Age-dependent trends in the proportion of seropositive individuals in five of the districts discriminated the three districts with sustained low malaria prevalence from the two districts with higher transmission. CONCLUSIONS: Asymptomatic Plasmodium carriers were found to be substantially more prevalent than clinical cases in seven districts of Gia Lai province, and a third of the population had serological evidence of previous malaria exposure. The findings add knowledge on the extent of asymptomatic malaria and transmission for developing malaria elimination strategies for Vietnam.
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Malaria Falciparum , Malaria Vivax , Malaria , Adulto , Infecciones Asintomáticas/epidemiología , Estudios Transversales , Humanos , Malaria/epidemiología , Malaria Falciparum/epidemiología , Malaria Vivax/epidemiología , Masculino , Plasmodium falciparum , Plasmodium vivax , Prevalencia , Estudios Seroepidemiológicos , Vietnam/epidemiologíaRESUMEN
BACKGROUND: With the decline in local malaria transmission in Vietnam as a result of the National Malaria Control Program (NMCP) elimination activities, a greater focus on the importation and potential reintroduction of transmission are essential to support malaria elimination objectives. METHODS: We conducted a multi-method assessment of the demographics, epidemiology, and clinical characteristics of imported malaria among international laborers returning from African or Southeast Asian countries to Vietnam. Firstly, we conducted a retrospective review of hospital records of patients from January 2014 to December 2016. Secondly, we conducted a mixed-methods prospective study for malaria patients admitted to the study sites from January 2017 to May 2018 using a structured survey with blood sample collection for PCR analysis and in-depth interviews. Data triangulation of the qualitative and quantitative data was used during analysis. RESULTS: International laborers were young (median age 33.0 years IQR 28.0-39.5 years), predominantly male (92%) adults returning mostly from the African continent (84%) who stayed abroad for prolonged periods (median time 13.5 months; IQR 6.0-331.5 months) and were involved in occupations that exposed them to a higher risk of malaria infection. Epidemiological trends were also similar amongst study strands and included the importation of Plasmodium falciparum primarily from African countries and P. vivax from Southeast Asian countries. Of 11 P. malariae and P. ovale infections across two study strands, 10 were imported from the African continent. Participants in the qualitative arm demonstrated limited knowledge about malaria prior to travelling abroad, but reported knowledge transformation through personal or co-worker's experience while abroad. Interestingly, those who had a greater understanding of the severity of malaria presented to the hospital for treatment sooner than those who did not; median of 3 days (IQR 2.0-7.0 days) versus 5 days (IQR 4.0-9.5 days) respectively. CONCLUSION: To address the challenges to malaria elimination raised by a growing Vietnamese international labor force, consideration should be given to appropriately targeted interventions and malaria prevention strategies that cover key stages of migration including pre-departure education and awareness, in-country prevention and prophylaxis, and malaria screening upon return.
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Malaria Vivax , Malaria , Adulto , Femenino , Humanos , Malaria/tratamiento farmacológico , Malaria/epidemiología , Malaria/prevención & control , Malaria Vivax/epidemiología , Masculino , Plasmodium falciparum , Estudios Prospectivos , Vietnam/epidemiologíaRESUMEN
Plasmodium falciparum resistance to dihydroartemisinin-piperaquine has spread through the Greater Mekong Subregion to southwestern Vietnam. In 2018 to 2019, we collected 127 P. falciparum isolates from Dak Nong (36), Dak Lak (55), Gia Lai (13), and Kon Tum (23) provinces in Vietnam's Central Highlands and found parasites bearing the Pfkelch13 C580Y mutation and multiple plasmepsin 2/3 genes (mean prevalence, 17.9%; range, 4.3% to 27.8%), conferring resistance to dihydroartemisinin-piperaquine. This information is important for drug policy decisions in Vietnam.
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Antimaláricos , Malaria Falciparum , Malaria , Parásitos , Quinolinas , Animales , Antimaláricos/farmacología , Antimaláricos/uso terapéutico , Resistencia a Medicamentos/genética , Malaria/tratamiento farmacológico , Malaria Falciparum/tratamiento farmacológico , Malaria Falciparum/epidemiología , Malaria Falciparum/prevención & control , Plasmodium falciparum/genética , Proteínas Protozoarias/uso terapéutico , Quinolinas/farmacología , Quinolinas/uso terapéutico , Vietnam/epidemiologíaRESUMEN
The rise in Plasmodium falciparum resistance to dihydroartemisinin-piperaquine in Vietnam justifies the need to evaluate alternative artemisinin-based combination therapies. Between July 2018 and October 2019, a single-arm trial of pyronaridine-artesunate (Pyramax, PA) was conducted in Dak Nong province, Vietnam. PA (3-day course) was administered to adults and children infected with P. falciparum. PA was well tolerated by the participants. The proportion of patients with Day 42 PCR-corrected adequate clinical and parasitological response was 95.2% (95% confidence interval [CI], 82.3 to 98.8, n = 40/42) for treating falciparum malaria. The median parasite clearance half-life was 6.7 h (range, 2.6 to 11.9) and the median parasite clearance time was 72 h (range, 12 to 132) with 44.9% (22/49) of patients having positive blood films at 72 h. The two patients that recrudesced had comparable Day 7 blood pyronaridine concentrations (39.5 and 39.0 ng/ml) to the 40 patients who did not recrudesce (median 43.4 ng/ml, 95% CI, 35.1 to 54.9). Ring-stage and piperaquine survival assays revealed that of the 29 P. falciparum isolates collected from the patients before PA treatment, 22 (75.9%) had reduced susceptibility to artemisinins and 17 (58.6%) were resistant to piperaquine. Genotyping confirmed that 92.0% (46/50) of falciparum patients were infected with parasites bearing the Pfkelch13 C580Y mutation associated with artemisinin resistance. Of these, 56.0% (28/50) of the isolates also had multiple copies of the plasmepsin 2/3 genes responsible for piperaquine resistance. Overall, PA was effective in treating P. falciparum in the Central Highlands of Vietnam. (This study has been registered at AustralianClinicalTrials.gov.au under trial ID ACTRN12618001429246.).
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Antimaláricos , Artemisininas , Malaria Falciparum , Quinolinas , Antimaláricos/farmacología , Antimaláricos/uso terapéutico , Artemisininas/uso terapéutico , Artesunato , Combinación de Medicamentos , Humanos , Malaria Falciparum/tratamiento farmacológico , Naftiridinas , Plasmodium falciparum/genética , Quinolinas/uso terapéutico , VietnamRESUMEN
BACKGROUND: Immunization with attenuated malaria sporozoites protects humans from experimental malaria challenge by mosquito bite. Protection in humans is strongly correlated with the production of T cells targeting a heterogeneous population of pre-erythrocyte antigen proteoforms, including liver stage antigens. Currently, few T cell epitopes derived from Plasmodium falciparum, the major aetiologic agent of malaria in humans are known. METHODS: In this study both in vitro and in vivo malaria liver stage models were used to sequence host and pathogen proteoforms. Proteoforms from these diverse models were subjected to mild acid elution (of soluble forms), multi-dimensional fractionation, tandem mass spectrometry, and top-down bioinformatics analysis to identify proteoforms in their intact state. RESULTS: These results identify a group of host and malaria liver stage proteoforms that meet a 5% false discovery rate threshold. CONCLUSIONS: This work provides proof-of-concept for the validity of this mass spectrometry/bioinformatic approach for future studies seeking to reveal malaria liver stage antigens towards vaccine development.
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Hígado/parasitología , Malaria Falciparum/inmunología , Plasmodium falciparum/inmunología , Animales , Antígenos de Protozoos/inmunología , Modelos Animales de Enfermedad , Epítopos de Linfocito T , Femenino , Hepatocitos , Inmunidad Celular , Vacunas contra la Malaria/inmunología , Malaria Falciparum/prevención & control , Espectrometría de Masas , Ratones , Proteómica , Albúmina Sérica HumanaRESUMEN
BACKGROUND: Individuals that work and sleep in remote forest and farm locations in the Greater Mekong Subregion continue to remain at high risk of both acquiring and transmitting malaria. These difficult-to-access population groups largely fall outside the reach of traditional village-centered interventions, presenting operational challenges for malaria programs. In Vietnam, over 60% of malaria cases are thought to be individuals who sleep in forests or on farms. New malaria elimination strategies are needed in countries where mobile and migrant workers frequently sleep outside of their homes. The aim of this study was to apply targeted surveillance-response based investigative approaches to gather location-specific data on confirmed malaria cases, with an objective to identify associated malaria prevention, treatment and risk behaviors of individuals sleeping in remote forest and farms sites in Vietnam. METHODS: A cross-sectional study using novel targeted reactive investigative approaches at remote area sleeping sites was conducted in three mountainous communes in Phu Yen province in 2016. Index cases were defined as individuals routinely sleeping in forests or farms who had tested positive for malaria. Index cases and non-infected neighbors from forest and farm huts within 500 m of the established sleeping locations of index cases were interviewed at their remote-area sleeping sites. RESULTS: A total of 307 participants, 110 index cases and 197 neighbors, were enrolled. Among 93 participants who slept in the forest, index cases were more likely to make > 5 trips to the forest per year (prevalence odds ratio (POR) 7.41, 95% confidence interval (CI) 2.66-20.63), sleep in huts without walls (POR 44.00, 95% CI 13.05-148.33), sleep without mosquito nets (POR 2.95, 95% CI 1.26-6.92), and work after dark (POR 5.48, 95% CI 1.84-16.35). Of the 204 farm-based respondents, a significantly higher proportion of index cases were involved in non-farming activities (logging) (POR 2.74, 95% CI 1.27-5.91). CONCLUSION: Investigative approaches employed in this study allowed for the effective recruitment and characterization of high-priority individuals frequently sleeping in remote forest and farm locations, providing relevant population and site-specific data that decision makers can use to design and implement targeted interventions to support malaria elimination.
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Bosques , Malaria/epidemiología , Malaria/transmisión , Adulto , Terapia Conductista , Estudios Transversales , Granjas , Femenino , Vivienda , Humanos , Malaria/tratamiento farmacológico , Malaria/prevención & control , Masculino , Persona de Mediana Edad , Mosquiteros , Oportunidad Relativa , Asunción de Riesgos , Vietnam/epidemiología , Vietnam/etnologíaRESUMEN
During 2010-2012, an outbreak of 210 cases of malaria occurred in Tumbes, in the northern coast of Peru, where no Plasmodium falciparum malaria case had been reported since 2006. To identify the source of the parasite causing this outbreak, we conducted a molecular epidemiology investigation. Microsatellite typing showed an identical genotype in all 54 available isolates. This genotype was also identical to that of parasites isolated in 2010 in the Loreto region of the Peruvian Amazon and closely related to clonet B, a parasite lineage previously reported in the Amazon during 1998-2000. These findings are consistent with travel history of index case-patients. DNA sequencing revealed mutations in the Pfdhfr, Pfdhps, Pfcrt, and Pfmdr1 loci, which are strongly associated with resistance to chloroquine and sulfadoxine/pyrimethamine, and deletion of the Pfhrp2 gene. These results highlight the need for timely molecular epidemiology investigations to trace the parasite source during malaria reintroduction events.
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Brotes de Enfermedades , Malaria Falciparum/epidemiología , Malaria Falciparum/parasitología , Plasmodium falciparum/genética , Alelos , Antimaláricos/farmacología , ADN Protozoario , Resistencia a Medicamentos , Eliminación de Gen , Genotipo , Geografía , Haplotipos , Historia del Siglo XXI , Humanos , Malaria Falciparum/historia , Repeticiones de Microsatélite , Epidemiología Molecular , Perú/epidemiología , Plasmodium falciparum/efectos de los fármacos , Proteínas Protozoarias/genéticaRESUMEN
The prevalence of obesity has reached epidemic proportions and is associated with several co-morbid conditions including diabetes, dyslipidemia, cancer, atherosclerosis and gallstones. Obesity is associated with low systemic inflammation and an accumulation of adipose tissue macrophages (ATMs) that are thought to modulate insulin resistance. ATMs may also modulate adipocyte metabolism and take up lipids released during adipocyte lipolysis and cell death. We suggest that high levels of free cholesterol residing in adipocytes are released during these processes and contribute to ATM activation and accumulation during obesity and caloric restriction. Db/db mice were studied for extent of adipose tissue inflammation under feeding conditions of ad libitum (AL) and caloric restriction (CR). The major finding was a marked elevation in epididymal adipose ABCG1 mRNA levels with obesity and CR (6-fold and 16-fold, respectively) over that seen for lean wild-type mice. ABCG1 protein was also elevated for CR as compared to AL adipose tissue. ABCG1 is likely produced by cholesterol loaded ATMs since this gene is not highly expressed in adipocytes and ABCG1 expression is sterol mediated. Our data supports the concept that metabolic changes in adipocytes due to demand lipolysis and cell death lead to cholesterol loading of ATMs. Based on finding cholesterol-loaded peritoneal leukocytes with elevated levels of ABCG1 in CR as compared to AL mice, we suggest that pathways for cholesterol trafficking out of adipose tissue involve ATM egress as well as ABCG1 mediated cholesterol efflux. This article is part of a Special Issue entitled Advances in High Density Lipoprotein Formation and Metabolism: A Tribute to John F. Oram (1945-2010).
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Transportadoras de Casetes de Unión a ATP/metabolismo , Grasa Abdominal/metabolismo , Expresión Génica , Lipoproteínas/metabolismo , Obesidad/metabolismo , Pérdida de Peso , Transportador de Casetes de Unión a ATP, Subfamilia G, Miembro 1 , Transportadoras de Casetes de Unión a ATP/genética , Grasa Abdominal/patología , Adipocitos Blancos/metabolismo , Adipocitos Blancos/patología , Animales , Antígenos CD/metabolismo , Antígenos de Diferenciación Mielomonocítica/metabolismo , Restricción Calórica , Movimiento Celular , Colesterol/metabolismo , Femenino , Lipólisis , Lipoproteínas/genética , Macrófagos/enzimología , Macrófagos/metabolismo , Macrófagos/patología , Ratones , Ratones Endogámicos C57BL , Ratones Obesos , Óxido Nítrico Sintasa de Tipo II/metabolismo , Obesidad/dietoterapia , Obesidad/fisiopatología , Triglicéridos/metabolismoRESUMEN
Introduction: A highly efficacious and durable vaccine against malaria is an essential tool for global malaria eradication. One of the promising strategies to develop such a vaccine is to induce robust CD8+ T cell mediated immunity against malaria liver-stage parasites. Methods: Here we describe a novel malaria vaccine platform based on a secreted form of the heat shock protein, gp96-immunoglobulin, (gp96-Ig) to induce malaria antigen specific, memory CD8+ T cells. Gp96-Ig acts as an adjuvant to activate antigen presenting cells (APCs) and chaperone peptides/antigens to APCs for cross presentation to CD8+ T cells. Results: Our study shows that vaccination of mice and rhesus monkeys with HEK-293 cells transfected with gp96-Ig and two well-known Plasmodium falciparum CSP and AMA1 (PfCA) vaccine candidate antigens, induces liver-infiltrating, antigen specific, memory CD8+ T cell responses. The majority of the intrahepatic CSP and AMA1 specific CD8+ T cells expressed CD69 and CXCR3, the hallmark of tissue resident memory T cells (Trm). Also, we found intrahepatic, antigen-specific memory CD8+ T cells secreting IL-2, which is relevant for maintenance of effective memory responses in the liver. Discussion: Our novel gp96-Ig malaria vaccine strategy represents a unique approach to induce liver-homing, antigen-specific CD8+ T cells critical for Plasmodium liver-stage protection.
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Vacunas contra la Malaria , Malaria Falciparum , Malaria , Humanos , Proteínas de Choque Térmico/metabolismo , Células HEK293 , Linfocitos T CD8-positivos , Inmunoglobulinas/metabolismo , Antígenos de Protozoos , Malaria/prevención & control , Malaria/metabolismoRESUMEN
Lymphotoxin-α (LTα) is secreted by lymphocytes and acts through tumor necrosis factor-α receptors and the LTß receptor. Our goals were to determine whether LT has a role in obesity and investigate whether LT contributes to the link between obesity and adipose tissue lymphocyte accumulation. LT deficient (LT(-/-)) and wild-type (WT) mice were fed standard pelleted rodent chow or a high-fat/high-sucrose diet (HFHS) for 13 wk. Body weight, body composition, and food intake were measured. Glucose tolerance was assessed. Systemic and adipose tissue inflammatory statuses were evaluated by quantifying plasma adipokine levels and tissue macrophage and T cell-specific gene expression in abdominal fat. LT(-/-) mice were smaller (20%) and leaner (25%) than WT controls after 13 wk of HFHS diet feeding. LT(-/-) mice showed improved glucose tolerance, suggesting that, in WT mice, LT may impair glucose metabolism. Surprisingly, adipose tissue from rodent chow- and HFHS-fed LT(-/-) mice exhibited increased T lymphocyte and macrophage infiltration compared with WT mice. Despite the fact that LT(-/-) mice exhibited an enhanced inflammatory status at the systemic and tissue level even when fed rodent chow, they were protected from enhanced diet-induced obesity and insulin resistance. Thus, LT contributes to body weight and adiposity and is required to modulate the accumulation of immune cells in adipose tissue.
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Tejido Adiposo Blanco/inmunología , Linfotoxina-alfa/metabolismo , Macrófagos/inmunología , Obesidad/inmunología , Linfocitos T/inmunología , Adipoquinas/sangre , Adiposidad , Animales , Línea Celular , Citocinas/genética , Citocinas/metabolismo , Dieta Alta en Grasa/efectos adversos , Sacarosa en la Dieta/efectos adversos , Expresión Génica , Regulación de la Expresión Génica , Intolerancia a la Glucosa/sangre , Intolerancia a la Glucosa/etiología , Intolerancia a la Glucosa/inmunología , Intolerancia a la Glucosa/metabolismo , Resistencia a la Insulina , Linfotoxina-alfa/genética , Macrófagos/metabolismo , Masculino , Ratones , Ratones Noqueados , Obesidad/sangre , Obesidad/etiología , Obesidad/metabolismo , ARN Mensajero/metabolismo , Distribución Aleatoria , Linfocitos T/metabolismo , Aumento de PesoRESUMEN
BACKGROUND: Acute febrile illness is a common presentation for patients at hospitals globally. Assays that can diagnose a variety of common pathogens in blood could help to establish a diagnosis for targeted disease management. We aimed to evaluate the performance of the BioFire Global Fever Panel (GF Panel), a multiplex nucleic acid amplification test performed on whole blood specimens run on the BioFire FilmArray System, in the diagnosis of several pathogens that cause acute febrile illness. METHODS: We did a prospective, multicentre, cross-sectional diagnostic accuracy study to evaluate the GF Panel. Consenting adults and children older than 6 months presenting with fever in the previous 2 days were enrolled consecutively in sub-Saharan Africa (Ghana, Kenya, Tanzania, Uganda), southeast Asia (Cambodia, Thailand), central and South America (Honduras, Peru), and the USA (Washington, DC; St Louis, MO). We assessed the performance of six analytes (chikungunya virus, dengue virus [serotypes 1-4], Leptospira spp, Plasmodium spp, Plasmodium falciparum, and Plasmodium vivax or Plasmodium ovale) on the GF Panel. The performance of the GF Panel was assessed using comparator PCR assays with different primers followed by bidirectional sequencing on nucleic acid extracts from the same specimen. We calculated the positive percent agreement and negative percent agreement of the GF Panel with respect to the comparator assays. This study is registered with ClinicalTrials.gov, NCT02968355. FINDINGS: From March 26, 2018, to Sept 30, 2019, 1965 participants were enrolled at ten sites worldwide. Of the 1875 participants with analysable results, 980 (52·3%) were female and the median age was 22 years (range 0-100). At least one analyte was detected in 657 (35·0%) of 1875 specimens. The GF Panel had a positive percent agreement for the six analytes evaluated as follows: chikungunya virus 100% (95% CI 86·3-100), dengue virus 94·0% (90·6-96·5), Leptospira spp 93·8% (69·8-99·8), Plasmodium spp 98·3% (96·3-99·4), P falciparum 92·7% (88·8-95·6), and P vivax or P ovale 92·7% (86·7-96·6). The GF Panel had a negative percent agreement equal to or greater than 99·2% (98·6-99·6) for all analytes. INTERPRETATION: This 1 h sample-to-answer, molecular device can detect common causative agents of acute febrile illness with excellent positive percent agreement and negative percent agreement directly in whole blood. The targets of the assay are prevalent in tropical and subtropical regions globally, and the assay could help to provide both public health surveillance and individual diagnoses. FUNDING: BioFire Defense, Joint Project Manager for Medical Countermeasure Systems and US Army Medical Materiel Development Activity, and National Institute of Allergy and Infectious Diseases.
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Fiebre Chikungunya , Virus Chikungunya , Dengue , Leptospirosis , Malaria , Plasmodium , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Niño , Preescolar , Estudios Transversales , Femenino , Fiebre , Humanos , Lactante , Recién Nacido , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Adulto JovenRESUMEN
Asymptomatic parasite carriers represent a "silent" infective reservoir for malaria transmission and contributes to malaria persistence. However, limited data are available on asymptomatic malaria in Vietnam. Between November 2018 and March 2019, we conducted a malaria epidemiological survey of asymptomatic people (children ≥ 10 years old and adults ≥18 years old, n = 2,809) residing in three communes in Tuy Duc district, Dak Nong province in the Central Highlands of Vietnam. Based on the national stratification of malaria risk, Dak Buk So, Dak Ngo and Quang Truc communes were classified by the National Malaria Control Programme as low, moderate and high malaria endemic areas, respectively. Using participants' finger prick blood samples, malaria parasites were detected by one-step reverse transcription-quantitative polymerase chain reaction (RT-qPCR). The median age (Interquartile Range) for adults and children were 35 years (26-50) and 12 years (11-14), respectively. The prevalence of asymptomatic malaria was 1.7% (22/1,328), 3.5% (31/890) and 12.2% (72/591) for participants from Dak Buk So, Dak Ngo and Quang Truc, respectively. The prevalence of asymptomatic malaria was lower in children compared to adults: 2.6% (9/352) versus 4.7% (116/2,457) (Odds Ratio 0.53, 95% Confidence Interval 0.28 to1.02). Ownership of long-lasting insecticide-treated bed nets and hammocks was 97.1%, 99.0% and 94.7% for participants in Dak Buk So, Dak Ngo and Quang Truc, respectively, however, only 66.0%, 57.3% and 42.8% of the participants reported using bed nets every night. Of the several risk factors examined, going to the forest two weeks prior to enrolment into the study and sleeping in the forest had a significant association with participants being infected with asymptomatic malaria in Quang Truc, but not in the other two communes. Knowledge of the prevalence and distribution of asymptomatic malaria will help design and evaluate future intervention strategies for malaria elimination in Vietnam.
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Malaria Falciparum , Adolescente , Adulto , Niño , Preescolar , Humanos , Masculino , Adulto JovenRESUMEN
In-line with the World Health Organization's (WHO) Global Technical Strategy for Malaria (2016-2030), Vietnam is striving to eliminate malaria by 2030. Targeting appropriate interventions in high-risk populations such as forest and forest-fringe communities is a critical component of malaria elimination efforts in Vietnam. In 2016, a household-level malaria indicator survey was conducted in Phu Yen Province, Vietnam with the aim of assessing the knowledge, behaviors and associated risks of malaria infection among priority mobile and migrant populations (MMPs) working and sleeping in forests and on farms. A total of 4211 people were included in the survey, comprised of 1074 heads of households and 3137 associated household members. Of the 1074 head-of-household respondents, 472 slept in a forest, 92 slept on a farm, 132 slept in both forests and farms, and 378 slept at their villages within the last 12 months. Age, literacy, and occupation were significantly different among those who slept in a forest versus on a farm. Of 301 respondents who answered questions about malaria risk factors at sleeping sites, 35% were somewhat aware of malaria prevention practices, but only 4% could recall at least four malaria prevention messages. Among the same group of 301 respondents, only 29% used nets and only 11% used treated nets. Ownership and use of nets among forest-goers was significantly lower than those who slept on a farm or in their village. Huts without walls were significantly prominent forest sleeping site locations (POR = 10.3; 95% CI 4.67-22.7). All respondents who slept in a forest requested standby malaria drugs and one-third of them self-treated without blood testing. Results from this study highlight the importance of capturing relevant location-specific data among priority populations such as remote forest and farm going mobile and migrant populations in Vietnam. Data regarding behavioral practices, knowledge, preventative measures, and intervention coverage at remote-area transmission sites must be routinely captured to effectively monitor progress and refine targeted intervention strategies accordingly.
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Malaria/epidemiología , Malaria/prevención & control , Malaria/transmisión , Adulto , Estudios Transversales , Biomarcadores Ambientales , Composición Familiar , Granjas , Femenino , Bosques , Humanos , Masculino , Persona de Mediana Edad , Factores de Riesgo , Encuestas y Cuestionarios , Migrantes/estadística & datos numéricos , Vietnam/epidemiologíaRESUMEN
Strengthening vector control measures among mobile and migrant populations (MMPs) is crucial to malaria elimination, particularly in areas with multidrug-resistant malaria. Although a global priority, providing access and ensuring high coverage of available tools such as long-lasting insecticidal nets (LLINs) among these vulnerable groups remains a significant challenge. We assessed mosquito net ownership, utilization, and preference among individuals who slept in a forest and/or on a farm against those residing only in village "home" settings in a priority malaria elimination area of Vietnam. Proportions of respondents owning bed nets were similar among forest, farm, and home sleeping sites, ranging between 96% and 98%. The proportion of respondents owning hammock nets was higher for the forest group (92%), whereas ownership of hammocks in general was significantly lower for the home group (55%). Most respondents (97%) preferred to bring hammock nets to their remote sleeping site, whereas a smaller proportion (25%) also considered bed nets as an option. Respondent preferences included thick hammock nets with zippers (53%), hammocks with a flip cover (17%), and thin hammock nets with zippers (15%), with none choosing polyethylene (hard) LLINs. Although there is high coverage and access to nets for this high-priority MMP group, there was a noted gap between coverage and net use, potentially undermining the effectiveness of net-related interventions that could impact malaria prevention and elimination efforts in Vietnam. The design and material of nets are important factors for user preferences that appear to drive net use.
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Mosquiteros Tratados con Insecticida/provisión & distribución , Malaria/prevención & control , Control de Mosquitos/métodos , Propiedad/estadística & datos numéricos , Migrantes/psicología , Estudios Transversales , Granjas , Humanos , Malaria/epidemiología , Encuestas y Cuestionarios , Vietnam/epidemiologíaRESUMEN
The development of a sterilizing vaccine against malaria remains one of the highest priorities for global health research. While sporozoite vaccines targeting the pre-erythrocytic stage show great promise, it has not been possible to maintain efficacy long-term, likely due to an inability of these vaccines to maintain effector memory T cell responses in the liver. Vaccines based on human cytomegalovirus (HCMV) might overcome this limitation since vectors based on rhesus CMV (RhCMV), the homologous virus in rhesus macaques (RM), elicit and indefinitely maintain high frequency, non-exhausted effector memory T cells in extralymphoid tissues, including the liver. Moreover, RhCMV strain 68-1 elicits CD8+ T cells broadly recognizing unconventional epitopes exclusively restricted by MHC-II and MHC-E. To evaluate the potential of these unique immune responses to protect against malaria, we expressed four Plasmodium knowlesi (Pk) antigens (CSP, AMA1, SSP2/TRAP, MSP1c) in RhCMV 68-1 or in Rh189-deleted 68-1, which additionally elicits canonical MHC-Ia-restricted CD8+ T cells. Upon inoculation of RM with either of these Pk Ag expressing RhCMV vaccines, we obtained T cell responses to each of the four Pk antigens. Upon challenge with Pk sporozoites we observed a delayed appearance of blood stage parasites in vaccinated RM consistent with a 75-80% reduction of parasite release from the liver. Moreover, the Rh189-deleted RhCMV/Pk vectors elicited sterile protection in one RM. Once in the blood, parasite growth was not affected. In contrast to T cell responses induced by Pk infection, RhCMV vectors maintained sustained T cell responses to all four malaria antigens in the liver post-challenge. The delayed appearance of blood stage parasites is thus likely due to a T cell-mediated inhibition of liver stage parasite development. As such, this vaccine approach can be used to efficiently test new T cell antigens, improve current vaccines targeting the liver stage and complement vaccines targeting erythrocytic antigens.
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Antígenos de Protozoos/inmunología , Citomegalovirus/genética , Vacunas contra la Malaria/inmunología , Malaria/inmunología , Parasitemia/inmunología , Plasmodium knowlesi/inmunología , Esporozoítos/inmunología , Animales , Anopheles/inmunología , Anopheles/parasitología , Femenino , Vectores Genéticos/administración & dosificación , Memoria Inmunológica , Hígado/inmunología , Hígado/parasitología , Macaca mulatta , Malaria/sangre , Malaria/parasitología , Malaria/prevención & control , Masculino , Parasitemia/sangre , Parasitemia/parasitología , Parasitemia/prevención & control , Plasmodium knowlesi/genética , Proteínas Protozoarias/inmunología , Linfocitos T/inmunología , Linfocitos T/parasitologíaRESUMEN
In the Peruvian North Coast (PNC), the number of Plasmodium vivax malaria cases increased steadily from 2007 to 2010 despite a significant decline in the overall number of cases in Peru during the same period. To better understand the transmission dynamics of P. vivax populations in the PNC and the neighboring Ecuadorian Amazon Basin (EAB), we studied the genetic variability and population structure of P. vivax in these areas. One hundred and twenty P. vivax isolates (58 from Piura and 37 from Tumbes in the PNC collected from 2008 to 2010 and 25 from the EAB collected in Pastaza from 2001 to 2004) were assessed by five polymorphic microsatellite markers. Genetic variability was determined by expected heterozygosity (He) and population structure by Bayesian inference cluster analysis. We found very low genetic diversity in the PNC (He = 0-0.32) but high genetic diversity in the EAB (He = 0.43-0.70). Population structure analysis revealed three distinct populations in the three locations. Six of 37 (16%) isolates from Tumbes had an identical haplotype to that found in Piura, suggesting unidirectional flow from Piura to Tumbes. In addition, one haplotype from Tumbes showed similarity to a haplotype found in Pastaza, suggesting that this could be an imported case from EAB. These findings strongly suggest a minimal population flow and different levels of genetic variability between these two areas divided by the Andes Mountains. This work presents molecular markers that could be used to increase our understanding of regional malaria transmission dynamics, which has implications for the development of strategies for P. vivax control.
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ADN Protozoario/genética , Flujo Génico , Variación Genética , Malaria Vivax/epidemiología , Plasmodium vivax/genética , Teorema de Bayes , Ecuador/epidemiología , Haplotipos , Humanos , Malaria Vivax/diagnóstico , Malaria Vivax/parasitología , Repeticiones de Microsatélite , Perú/epidemiología , Filogeografía , Plasmodium vivax/clasificaciónRESUMEN
The reemergence of malaria in the last decade in Madre de Dios, southern Peruvian Amazon basin, was accompanied by ecological, political, and socioeconomic changes related to the proliferation of illegal gold mining. We conducted a secondary analysis of passive malaria surveillance data reported by the health networks in Madre de Dios between 2001 and 2012. We calculated the number of cases of malaria by year, geographic location, intensity of illegal mining activities, and proximity of health facilities to the Peru-Brazil Interoceanic Highway. During 2001-2012, 203,773 febrile cases were identified in Madre de Dios, of which 30,811 (15.1%) were confirmed cases of malaria; all but 10 cases were due to Plasmodium vivax Cases of malaria rose rapidly between 2004 and 2007, reached 4,469 cases in 2005, and then declined after 2010 to pre-2004 levels. Health facilities located in areas of intense illegal gold mining reported 30-fold more cases than those in non-mining areas (ratio = 31.54, 95% confidence interval [CI] = 19.28, 51.60). Finally, health facilities located > 1 km from the Interoceanic Highway reported significantly more cases than health facilities within this distance (ratio = 16.20, 95% CI = 8.25, 31.80). Transmission of malaria in Madre de Dios is unstable, geographically heterogeneous, and strongly associated with illegal gold mining. These findings highlight the importance of spatially oriented interventions to control malaria in Madre de Dios, as well as the need for research on malaria transmission in illegal gold mining camps.
Asunto(s)
Malaria/epidemiología , Minería , Adulto , Femenino , Oro , Humanos , Malaria/transmisión , Malaria Falciparum/epidemiología , Malaria Falciparum/transmisión , Malaria Vivax/epidemiología , Malaria Vivax/transmisión , Masculino , Perú/epidemiología , Estaciones del AñoRESUMEN
BACKGROUND: Malaria and dengue are two of the most common vector-borne diseases in the world, but co-infection is rarely described, and immunologic comparisons of co-infection with mono-infection are lacking. METHODOLOGY AND PRINCIPAL FINDINGS: We collected symptom histories and blood specimens from subjects in a febrile illness surveillance study conducted in Iquitos and Puerto Maldonado, Peru, between 2002-2011. Nineteen symptoms and 18 immune markers at presentation were compared among those with co-infection with Plasmodium/dengue virus (DENV), Plasmodium mono-infection, and DENV mono-infection. Seventeen subjects were identified as having Plasmodium/DENV co-infection and were retrospectively matched with 51 DENV mono-infected and 44 Plasmodium mono-infected subjects. Those with Plasmodium mono-infection had higher levels of IL-4, IL-6, IL-10, IL-12, IL-13, IL-17A, IFN-γ, and MIP1-α/CCL3 compared with DENV mono-infection or co-infection; those with Plasmodium mono-infection had more cough than those with DENV mono-infection. Subjects with DENV mono-infection had higher levels of TGF-ß1 and more myalgia than those with Plasmodium mono-infection. No symptom was more common and no immune marker level was higher in the co-infected group, which had similar findings to the DENV mono-infected subjects. CONCLUSIONS/SIGNIFICANCE: Compared with mono-infection with either pathogen, Plasmodium/DENV co-infection was not associated with worse disease and resembled DENV mono-infection in both symptom frequency and immune marker level.