Showing papers on "Plasmodium vivax published in 2004"
TL;DR: This review supports a recommendation for a regimen of 0.5 mg/kg primaquine daily for 14 days, on the basis of superior efficacy and good tolerability and safety in nonpregnant persons without glucose-6-phosphate dehydrogenase deficiency.
Abstract: Primaquine is the only available drug for preventing relapse of malaria, and confusion surrounds its use. This review examines the wide range of clinical applications of primaquine described in the medical literature between 1946 and 2004. The risk of relapse of Plasmodium vivax malaria without primaquine therapy ranged from 5% to 80% or more, depending largely upon geographic location. Supervision of therapy profoundly impacts the risk of relapse, and almost all reports of malaria resistant to primaquine are associated with lack of such supervision. We nonetheless suspect that there is widespread resistance to the standard course of primaquine therapy, which is 15 mg primaquine base daily for 14 days. Clinical evidence confirms that a course of 15 mg daily for just 5 days, a regimen widely used in areas where malaria is endemic, has no discernible efficacy. This review supports a recommendation for a regimen of 0.5 mg/kg primaquine daily for 14 days, on the basis of superior efficacy and good tolerability and safety in nonpregnant persons without glucose-6-phosphate dehydrogenase deficiency.
421 citations
TL;DR: This minireview summarizes the present state of knowledge of CRPV as a scientific, clinical, and public health problem and examines the genesis of CQ therapy for P. vivax and the laboratory and clinical data underpinning the diagnosis.
Abstract: Emerging resistance to chloroquine (CQ) by Plasmodium vivax threatens the health of the hundreds of millions of people routinely exposed to the risk of infection with this organism. CQ has been the first-line therapy for vivax malaria since 1946 (32, 115). Plasmodium falciparum developed resistance to CQ in the 1950s (110), and today it occurs globally (91). Resistance by P. vivax was unknown until 1989, when Australians repatriated from Papua New Guinea failed routine treatment (94). Subsequent reports affirmed that finding, and CQ-resistant P. vivax (CRPV) was reported from Indonesia (8, 35, 99, 100, 111). Reports from Myanmar (76, 82) and India (56, 107) followed. CRPV appeared in travelers from Guyana, South America (88). However, studies in Thailand (38, 72, 103), the Philippines (10), and Vietnam (105) revealed only CQ-sensitive P. vivax. Surveys in Indonesia revealed a low frequency of CRPV in the west (∼10%) (15, 16, 49, 50, 51, 53, 75) and a higher risk in the east (∼45%) (9, 18, 52, 81, 102, 106). This minireview summarizes the present state of knowledge of CRPV as a scientific, clinical, and public health problem. It examines the genesis of CQ therapy for P. vivax and the laboratory and clinical data underpinning the diagnosis of CRPV. The available data showing the global distribution of CRPV are listed. Finally, the clinical data on alternative therapies against CRPV are reviewed.
345 citations
TL;DR: A TaqMan-based real-time PCR qualitative assay for the detection of three species of malaria parasites was devised and evaluated using 122 whole-blood samples from patients who had traveled to areas where malaria is endemic and who presented with malaria-like symptoms and fever.
Abstract: A TaqMan-based real-time PCR qualitative assay for the detection of three species of malaria parasites—Plasmodium falciparum, P. ovale, and P. vivax—was devised and evaluated using 122 whole-blood samples from patients who had traveled to areas where malaria is endemic and who presented with malaria-like symptoms and fever. The assay was compared to conventional microscopy and to an established nested-PCR assay. The specificity of the new assay was confirmed by sequencing the PCR products from all the positive samples and by the lack of cross-reactivity with Toxoplasma gondii and Leishmania infantum DNA. Real-time PCR assay showed a detection limit (analytical sensitivity) of 0.7, 4, and 1.5 parasites/μl for P. falciparum, P. vivax, and P. ovale, respectively. Real-time PCR, like nested PCR, brought to light errors in the species identification by microscopic examination and revealed the presence of mixed infections (P. falciparum plus P. ovale). Real-time PCR can yield results within 2 h, does not require post-PCR processing, reduces sample handling, and minimizes the risks of contamination. The assay can therefore be easily implemented in routine diagnostic malaria tests. Future studies are warranted to investigate the clinical value of this technique.
326 citations
TL;DR: In epidemiological studies, a high prevalence of cryptic mixed-malaria species infection has been detected by sensitive PCR techniques and these interactions have important clinical and public health implications.
279 citations
TL;DR: Patients with malaria had traveled to sub-Saharan Africa more often, were more commonly visiting friends/relatives, had traveled for longer periods, presented sooner after return, wereMore likely to have a fever at presentation, and were lesslikely to have had a pretravel encounter.
Abstract: BACKGROUND Malaria is a common and important infection in travelers. METHODS We have examined data reported to the GeoSentinel surveillance network to highlight characteristics of malaria in travelers. RESULTS A total of 1140 malaria cases were reported (60% of cases were due to Plasmodium falciparum, 24% were due to Plasmodium vivax). Male subjects constituted 69% of the study population. The median duration of travel was 34 days; however, 37% of subjects had a travel duration of < or =4 weeks. The majority of travellers did not have a pretravel encounter with a health care provider. Most cases occurred in travelers (39%) or immigrants/refugees (38%). The most common reasons for travel were to visit friends/relatives (35%) or for tourism (26%). Three-quarters of infections were acquired in sub-Saharan Africa. Severe and/or complicated malaria occurred in 33 cases, with 3 deaths. Compared with others in the GeoSentinel database, patients with malaria had traveled to sub-Saharan Africa more often, were more commonly visiting friends/relatives, had traveled for longer periods, presented sooner after return, were more likely to have a fever at presentation, and were less likely to have had a pretravel encounter. In contrast to immigrants and visitors of friends or relatives, a higher proportion (73%) of the missionary/volunteer group who developed malaria had a pretravel encounter with a health care provider. Travel to sub-Saharan Africa and Oceania was associated with the greatest relative risk of acquiring malaria. CONCLUSIONS We have used a global database to identify patient and travel characteristics associated with malaria acquisition and characterized differences in patient type, destinations visited, travel duration, and malaria species acquired.
220 citations
TL;DR: Thrombocytopenia is identified as a key indicator of malaria in these febrile patients and changes in hematologic profiles for a semi-immune population are defined.
Abstract: This study examines hematologic profiles of persons with acute Plasmodium falciparum or P. vivax infection in Maesod on Thailand's western border with Myanmar compared with febrile, non-parasitemic persons also reporting to malaria clinics. Nine hundred seventy-nine subjects were malaria-negative, 414 were infected with P. falciparum, and 646 were infected with P. vivax. Persons with patent parasitemia tended to have significantly lower white blood cell, red blood cell, platelet, and hemoglobin levels than those who were malaria-negative. For the first time, a parallel trend in thrombocytopenia with parasitemia was found to be associated with both P. falciparum, and P. vivax infection. Using logistic regression, persons with platelet counts or = 150,000/microL. This study supplements previous literature on the hematologic effects of malaria and helps define those alterations for a semi-immune population. Thrombocytopenia is identified as a key indicator of malaria in these febrile patients.
217 citations
TL;DR: Seventy-seven surface-predicted residues of the Sal-1 DBL domain were substituted with alanine and assayed for erythrocyte binding activity by expression of the mutant proteins on the surface of transiently transfected COS cells, delineate DBLdomain residues essential for receptor recognition.
Abstract: Malaria merozoite invasion of human erythrocytes depends on recognition of specific erythrocyte surface receptors by parasite ligands. Plasmodium vivax merozoite invasion is totally dependent on the recognition of the Duffy blood group antigen by the parasite ligand Duffy-binding protein (DBP). Receptor recognition by P. vivax relies on a cysteine-rich domain, the DBL domain or region II, at the N terminus of the extracellular portion of DBP. The minimal region of the DBP implicated for receptor recognition lies between cysteines 4 and 8 of the DBL domain, which is a region that also has the highest rate of allelic polymorphisms among parasite isolates. We previously found that allelic polymorphisms in this region altered the P. vivax DBL domain antigenic character, which contrasts with changes in receptor specificity attributed to polymorphisms in some homologous ligands of Plasmodium falciparum. To further investigate the relative importance of conserved and polymorphic residues within this DBL central region, we identified residues critical for receptor recognition by site-directed mutagenesis. Seventy-seven surface-predicted residues of the Sal-1 DBL domain were substituted with alanine and assayed for erythrocyte binding activity by expression of the mutant proteins on the surface of transiently transfected COS cells. The functional effect of alanine substitution varied from nil to complete loss of DBL erythrocyte-binding activity. Mutations that caused loss of ligand function mostly occurred in discontinuous clusters of conserved residues, whereas nearly all mutations in polymorphic residues did not affect erythrocyte binding. These data delineate DBL domain residues essential for receptor recognition.
143 citations
TL;DR: The unique biology related to P. vivax transmission is reviewed and potential problems associated with the control of this parasite are addressed, which depends on an in-depth knowledge of malaria transmission.
128 citations
TL;DR: It is suggested that an ‘entente cordiale' between these two species might be beneficial both to parasites and humans, if this were the case, the influence of changes in the parasite formula in endemic areas on the burden of malaria would become an important element of study.
122 citations
TL;DR: Probabilistic modelling is used in conjunction with protein structural predictions and gene-structure analyses on a whole-genome scale to find gene homologies that are missed by conventional similarity-search strategies and identified a variant gene superfamily in six species of malaria (Plasmodium interspersed repeats, pir).
Abstract: Functionally related homologues of known genes can be difficult to identify in divergent species. In this paper, we show how multi-character analysis can be used to elucidate the relationships among divergent members of gene superfamilies. We used probabilistic modelling in conjunction with protein structural predictions and gene-structure analyses on a whole-genome scale to find gene homologies that are missed by conventional similarity-search strategies and identified a variant gene superfamily in six species of malaria (Plasmodium interspersed repeats, pir). The superfamily includes rif in P.falciparum, vir in P.vivax, a novel family kir in P.knowlesi and the cir/bir/yir family in three rodent malarias. Our data indicate that this is the major multi-gene family in malaria parasites. Protein localization of products from pir members to the infected erythrocyte membrane in the rodent malaria parasite P.chabaudi, demonstrates phenotypic similarity to the products of pir in other malaria species. The results give critical insight into the evolutionary adaptation of malaria parasites to their host and provide important data for comparative immunology between malaria parasites obtained from laboratory models and their human counterparts.
121 citations
TL;DR: Tafenoquine doses as low as a single 600-mg dose may be useful for prevention of relapse of P. vivax malaria in Thailand.
Abstract: Background. Tafenoquine is an 8-aminoquinoline developed as a more effective replacement for primaquine. In a previous dose-ranging study in Thailand, 3 tafenoquine regimens with total doses ranging from 500 mg to 3000 mg prevented relapse of Plasmodium vivax malaria in most patients when administered 2 days after receipt of a blood schizonticidal dose of chloroquine. Methods. To improve convenience and to begin comparison of tafenoquine with primaquine, 80 patients with P vivax infection were randomized to receive 1 of the following 5 treatments 1 day after receiving a blood schizonticidal dose of chloroquine: (A) tafenoquine, 300 mg per day for 7 days (n = 18); (B) tafenoquine, 600 mg per day for 3 days (n = 19); (C) tafenoquine, 600 mg as a single dose (n = 18); (D) no further treatment (n = 13); or (E) primaquine base, 15 mg per day for 14 days (n = 12). The minimum duration of protocol follow-up was 8 weeks, with additional follow-up to 24 weeks. Results. Forty-six of 55 tafenoquine recipients, 10 of 13 recipients of chloroquine only, and 12 of 12 recipients of chloroquine plus primaquine completed at least 8 weeks of follow-up (or had relapse). There was 1 relapse among recipients of chloroquine plus tafenoquine, 8 among recipients of chloroquine only, and 3 among recipients of chloroquine plus primaquine. The rate of protective efficacy (determined on the basis of reduction in incidence density) for all recipients of chloroquine plus tafenoquine, compared with recipients of chloroquine plus primaquine, was 92.6% (95% confidence interval, 7.3%-99.9%; P = .042, by Fisher's exact test). Conclusions. Tafenoquine doses as low as a single 600-mg dose may be useful for prevention of relapse of P. vivax malaria in Thailand.
TL;DR: Six P. falciparum DBL ligands JESEBL and BAEBL can recognize multiple receptors on the erythrocyte surface and may have been successful in endemic areas because it has mutated the ligands of the DBL family to create multiple pathways of invasion, thus making selection of refractory ERYthrocytes unlikely.
Abstract: The malaria parasite lives within erythrocytes and depends on the binding of parasite ligands to host cell surface receptors for invasion. The most virulent human malaria parasite, Plasmodium falciparum, uses multiple ligands, including EBA-175, BAEBL, and JESEBL of the Duffy-binding-like (DBL) family of erythrocyte-binding proteins, for invasion of human erythrocytes. Region II of these parasite ligands is the erythrocyte-binding domain. Previously, we had shown that polymorphism in region II of BAEBL leads to different erythrocyte-binding specificities. We have now identified and characterized the binding specificity of six JESEBL variants. We sequenced region II of JESEBL from 20 P. falciparum clones collected from various parts of the world where malaria is endemic. We observed eight JESEBL variants that contained amino acid polymorphisms at five positions among all clones. Seven of the eight variants could be connected by a single base change that led to an amino acid change. We investigated the functional significance of these polymorphisms by transiently expressing region II from six of JESEBL variants on the surface of Chinese hamster ovary cells. We observed four erythrocyte-binding patterns to enzyme-treated erythrocytes. Thus, P. falciparum DBL ligands JESEBL and BAEBL can recognize multiple receptors on the erythrocyte surface. In contrast to Plasmodium vivax, which has disappeared from West Africa because of the Duffy-negative blood group, P. falciparum may have been successful in endemic areas because it has mutated the ligands of the DBL family to create multiple pathways of invasion, thus making selection of refractory erythrocytes unlikely.
Humboldt University of Berlin1, Ludwig Maximilian University of Munich2, University of Copenhagen3, Institute of Tropical Medicine Antwerp4, Karolinska Institutet5, Bradford Royal Infirmary6, University of Brescia7, Carlos III Health Institute8, Massachusetts Institute of Technology9, University of Vienna10, Heidelberg University11, Hvidovre Hospital12, Gdańsk Medical University13, University of Ulm14, Helsinki University Central Hospital15, Haukeland University Hospital16, Universidade Nova de Lisboa17
TL;DR: TropNetEurop data can contribute to the harmonization of European treatment policies by focusing on disease frequency, patient characteristics, place of infection, course of disease, treatment and differences between network-member countries.
Abstract: Plasmodium vivax is the second most common species among malaria patients diagnosed in Europe, but epidemiological and clinical data on imported P. vivax malaria are limited. The TropNetEurop surveillance network has monitored the importation of vivax malaria into Europe since 1999. To present epidemiological and clinical data on imported P. vivax malaria collected at European level. Data of primary cases of P. vivax malaria reported between January 1999 and September 2003 were analysed, focusing on disease frequency, patient characteristics, place of infection, course of disease, treatment and differences between network-member countries. Within the surveillance period 4,801 cases of imported malaria were reported. 618 (12.9%) were attributed to P. vivax. European travellers and immigrants were the largest patient groups, but their proportion varied among the reporting countries. The main regions of infection in descending order were the Indian subcontinent, Indonesia, South America and Western and Eastern Africa, as a group accounting for more than 60% of the cases. Regular use of malaria chemoprophylaxis was reported by 118 patients. With 86 (inter-quartile range 41–158) versus 31 days (inter-quartile range 4–133) the median symptom onset was significantly delayed in patients with chemoprophylaxis (p < 0.0001). Common complaints were fever, headache, fatigue, and musculo-skeletal symptoms. All patients survived and severe clinical complications were rare. Hospitalization was provided for 60% and primaquine treatment administered to 83.8% of the patients, but frequencies varied strongly among reporting countries. TropNetEurop data can contribute to the harmonization of European treatment policies.
TL;DR: Sulfadoxine is predominantly used in combination with pyrimethamine, commonly known as Fansidar, for the treatment of Plasmodium falciparum, and is predicted by energy minimization to cause a reduction in binding of sulfadoxines to dihydropteroate synthase in P. vivax, probably due to the innate refractoriness of parasites to the sulfad oxine component.
Abstract: Sulfadoxine is predominantly used in combination with pyrimethamine, commonly known as Fansidar, for the treatment of Plasmodium falciparum. This combination is usually less effective against Plasmodium vivax, probably due to the innate refractoriness of parasites to the sulfadoxine component. To investigate this mechanism of resistance by P. vivax to sulfadoxine, we cloned and sequenced the P. vivax dhps (pvdhps) gene. The protein sequence was determined, and three-dimensional homology models of dihydropteroate synthase (DHPS) from P. vivax as well as P. falciparum were created. The docking of sulfadoxine to the two DHPS models allowed us to compare contact residues in the putative sulfadoxine-binding site in both species. The predicted sulfadoxine-binding sites between the species differ by one residue, V585 in P. vivax, equivalent to A613 in P. falciparum. V585 in P. vivax is predicted by energy minimization to cause a reduction in binding of sulfadoxine to DHPS in P. vivax compared to P. falciparum. Sequencing dhps genes from a limited set of geographically different P. vivax isolates revealed that V585 was present in all of the samples, suggesting that V585 may be responsible for innate resistance of P. vivax to sulfadoxine. Additionally, amino acid mutations were observed in some P. vivax isolates in positions known to cause resistance in P. falciparum, suggesting that, as in P. falciparum, these mutations are responsible for acquired increases in resistance of P. vivax to sulfadoxine.
TL;DR: It is inferred that the world expansion of P. vivax as a human parasite occurred recently, perhaps <10,000 years ago; the differential variability of the TRs may reflect selective processes acting on particular regions of the genome.
Abstract: Malaria is a major human parasitic disease caused by four species of Plasmodium protozoa. Plasmodium vivax, the most widespread, affects millions of people across Africa, Asia, the Middle East, and Central and South America. We have studied the genetic variability of 13 microsatellite loci in 108 samples from 8 localities in Asia, Africa, South America, and New Guinea. Only one locus is polymorphic; nine are completely monomorphic, and the remaining three are monomorphic in all but one or two populations, which have a rare second allele. In contrast, Plasmodium falciparum displays extensive microsatellite polymorphism within and among populations. We further have analyzed, in 96 samples from the same 8 localities, 8 tandem repeats (TRs) located on a 100-kb contiguous chromosome segment described as highly polymorphic. Each locus exhibits 2-10 alleles in the whole sample but little intrapopulation polymorphism (1-5 alleles with a prevailing allele in most cases). Eight microsatellite loci monomorphic in P. vivax are polymorphic in three of five Plasmodium species related to P. vivax (two to seven individuals sampled). Plasmodium simium, a parasite of New World monkeys, is genetically indistinguishable from P. vivax. At 13 microsatellite loci and at 7 of the 8 TRs, both species share the same (or most common) allele. Scarce microsatellite polymorphism may reflect selective sweeps or population bottlenecks in recent evolutionary history of P. vivax; the differential variability of the TRs may reflect selective processes acting on particular regions of the genome. We infer that the world expansion of P. vivax as a human parasite occurred recently, perhaps <10,000 years ago.
TL;DR: In this paper, the authors identified a strong correlation between specific mutations in P vivax dihydrofolate reductase (DHFR) and the failure of sulfadoxine/pyrimethamine (S/P) treatment failure.
Abstract: The target enzyme of pyrimethamine is dihydrofolate reductase (DHFR) but little is known about allelic variants of dhfr in Plasmodium vivax populations Still less is known about associations between specific alleles and the failure of sulfadoxine/pyrimethamine (S/P) to clear the erythrocytic stages of P vivax in vivo We studied P vivax dhfr mutations in 24 patients who received S/P therapy in Papua or Central Java Indonesia and we measured the resistance of the alleles in vitro in a dhfr yeast expression assay Results Fourteen (58%) of 24 patients had an inadequate therapeutic response Two of 6 alleles that were identified were novel One allele that expressed 4 point mutations (57L+58R+61M+117T) correlated with a high risk of therapeutic failure The 9 patients infected by P vivax carrying this allele proved 23 times more likely to experience early therapeutic failure compared with patients infected by P vivax carrying other alleles (P=003; 95% confidence interval 2–450) This allele also conferred high levels of pyrimethamine resistance in vitro The experimental antifolate WR99210 inhibited the allele in this system The present study identified a strong correlation between specific mutations in P vivax dhfr and S/P treatment failure Our results suggest that WR99210 could provide effective therapy for S/P-resistant P vivax (authors)
TL;DR: It can be concluded that in malarious areas of Thailand, double infection with P. falciparum and P. vivax is common affecting at least 25% of the patients and usually manifests as sequential illnesses, but can be suppressed by the slowly eliminated antimalarial drugs such as chloroquine and mefloquine.
TL;DR: Monthly tafenoquine was safe, well tolerated, and highly effective in preventing P. vivax and multidrug-resistant P. falciparum malaria in Thai soldiers during 6 months of prophylaxis.
Abstract: We assessed monthly doses of tafenoquine for preventing Plasmodium vivax and multidrug-resistant P. falciparum malaria. In a randomized, double-blind, placebo-controlled study, 205 Thai soldiers received either a loading dose of tafenoquine 400 mg (base) daily for 3 days, followed by single monthly 400-mg doses (n = 104), or placebo (n = 101), for up to 5 consecutive months. In volunteers completing follow-up (96 tafenoquine and 91 placebo recipients), there were 22 P. vivax, 8 P. falciparum, and 1 mixed infection. All infections except 1 P. vivax occurred in placebo recipients, giving tafenoquine a protective efficacy of 97% for all malaria (95% confidence interval [CI], 82%-99%), 96% for P. vivax malaria (95% CI, 76%-99%), and 100% for P. falciparum malaria (95% CI, 60%-100%). Monthly tafenoquine was safe, well tolerated, and highly effective in preventing P. vivax and multidrug-resistant P. falciparum malaria in Thai soldiers during 6 months of prophylaxis.
TL;DR: Systematic database searches identified 435 antimalarial drug treatment trials, involving 82,616 patients, conducted and published between 1966 and December 2002, with a recent rise in the proportion of trial enrolling children, and a tripling in the average number of patients recruited per trial.
Abstract: Systematic database searches identified 435 antimalarial drug treatment trials, involving 82 616 patients, conducted and published between 1966 and December 2002. Of these trials 72% were randomised; 64 (15%) trials involved severe malaria, 47 (11%) studied Plasmodium vivax , 3 Plasmodium malariae or Plasmodium ovale , and the remainder (74%) assessed treatment responses in uncomplicated falciparum malaria. Twelve trials (2.7%) specifically evaluated antimalarial treatments in pregnant women. Overall 49% of trials were conducted in Asia (29% from Thailand alone) and 42% in Africa. Half of all the patients studied had been in trials published in the past 7 years. There has been a recent rise in the proportion of trial enrolling children, and a tripling in the average number of patients recruited per trial (from approximately 100 in the 1970s to 300 currently). Chloroquine was given to over half the patients in antimalarial drug trials ( n =53552) compared with artemisinin derivatives ( n =12463), mefloquine-sulphadoxine-pyrimethamine ( n =9153), mefloquine ( n =5546) and sulphadoxine-pyrimethamine ( n =5909). The quality of safety and efficacy data for recently evaluated drugs contrasts with a relative paucity of data for older ‘established’ compounds.
TL;DR: The progress made in drug resistance research in malaria parasites over the past 20 years is summarised, emphasising the most recent developments in the genetics of drug resistance.
Abstract: Drug resistance is one of the major factors contributing to the resurgence of malaria, especially resistance to the most affordable drugs such as chloroquine and Fansidar, a combination drug of pyrimethamine and sulfadoxine. Understanding the mechanisms of such resistance and developing new treatments, including new drugs, are urgently needed. Great progress has been made recently in studying the mechanisms of drug action and drug resistance in malaria parasites, particularly in Plasmodium falciparum. These efforts are highlighted by the demonstration of mutations in the parasite dihydrofolate reductase and dihydropteroate synthase genes conferring resistance to pyrimethamine and sulfadoxine, respectively, and by the recent discovery of mutations in the gene coding for a putative transporter, PfCRT, conferring resistance to chloroquine. Mutations in a homologue of a human multiple-drug-resistant gene, pfmdr1, have also been shown to be associated with responses to multiple drugs. However, except in the case of resistance to antifolate drugs, the mechanisms of action and resistance to most drugs currently in use are essentially unknown or are being debated. Additionally, novel mechanisms of resistance exist in different malaria parasites, complicating the process of developing new drugs and treatment strategies. Here we summarise the progress made in drug resistance research in malaria parasites over the past 20 years, emphasising the most recent developments in the genetics of drug resistance.
TL;DR: The need of the development or use of a more accurate diagnosis method to distinguish between P. malariae and P. vivax is pointed to, which is particularly important in view of the fact that the choice of drug for the antimalarial therapy depends on the parasite species.
TL;DR: It is proposed that P. vivax specifically adhere to barrier cells in the human spleen allowing the parasite to escape spleen-clearance while favouring the release of merozoites in an environment where reticulocytes are stored before their release into circulation to compensate for the anaemia associated with v Vivax malaria.
TL;DR: Recombinant vivapain-2 and vivAPain-3 shared properties with the falcipains, including acidic pH optima, requirements for reducing conditions for activity and hydrolysis of substrates with positively charged residues at P1 and Leu at P2.
Abstract: Cysteine proteases play important roles in the life cycles of malaria parasites. Cysteine protease inhibitors block haemoglobin hydrolysis and development in Plasmodium falciparum, suggesting that the cysteine proteases of this major human pathogen, termed falcipains, are appropriate therapeutic targets. To expand our understanding of plasmodial proteases to Plasmodium vivax, the other prevalent human malaria parasite, we identified and cloned genes encoding the P. vivax cysteine proteases, vivapain-2 and vivapain-3, and functionally expressed the proteases in Escherichia coli. The vivapain-2 and vivapain-3 genes predicted papain-family cysteine proteases, which shared a number of unusual features with falcipain-2 and falcipain-3, including large prodomains and short N-terminal extensions on the catalytic domain. Recombinant vivapain-2 and vivapain-3 shared properties with the falcipains, including acidic pH optima, requirements for reducing conditions for activity and hydrolysis of substrates with positively charged residues at P1 and Leu at P2. Both enzymes hydrolysed native haemoglobin at acidic pH and the erythrocyte cytoskeletal protein 4.1 at neutral pH, suggesting similar biological roles to the falcipains. Considering inhibitor profiles, the vivapains were inhibited by fluoromethylketone and vinyl sulphone inhibitors that also inhibited falcipains and have demonstrated potent antimalarial activity.
TL;DR: There seems to be a high risk of therapeutic failure in patients given CQ to cure P. vivax malaria in Şanlıurfa province, in south–eastern Turkey, probably because of CQ resistance.
Abstract: In most regions of the world, chloroquine (CQ) has been the standard treatment for Plasmodium vivax malaria for more than 40 years. Recently, however, CQ-resistant P. vivax has been reported from Oceania, several parts of Asia, and South America. The therapeutic efficacy of CQ in the treatment of acute, P. vivax malaria has now been assessed in two areas of the Turkish province of Sanliurfa: the towns of Karacadag and Sekerli. On admission and on days 2, 3, 7, 14, 21, and 28, all 112 patients investigated were examined clinically and blood samples were collected and smeared. Treatment consisted of 10 mg CQ/kg on day 0, the same dose on day 1, and 5 mg CQ/mg on day 2, each dose being supervised. Worryingly, 14.7% of the patients from Karacadag and 10.3% of those from Sekerli showed apparent treatment failure between days 3 and 28. In Sanliurfa province, in south-eastern Turkey, there therefore seems to be a high risk of therapeutic failure in patients given CQ to cure P. vivax malaria, probably because of CQ resistance.
TL;DR: Immunodepletion studies with sera from mice immunized with these two antigens showed that while immunization with PvMSP-142 does produce a PvM SP-119-specific response, a substantial portion is also focused on structures in Pv merozoite surface protein 1 not represented by the epidermal growth factor-like domains of PvmSP-119.
Abstract: The proteins expressed on the surface of invasive merozoites of Plasmodium are important targets for the development of an effective malaria vaccine. Among these, merozoite surface protein 1 (MSP-1) is a leading malaria vaccine candidate antigen (32). For Plasmodium falciparum, it has been shown that MSP-1 is synthesized as a 195-kDa protein that is sequentially processed into a series of fragments (22). Of particular interest among these fragments are a cysteine-rich 19-kDa fragment (MSP-119) and a C-terminal 42-kDa fragment (MSP-142); the 19-kDa fragment forms part of the 42-kDa protein. Several in vitro and in vivo studies have provided evidence suggesting that these two fragments of MSP-1 are the targets of protective immunity against asexual blood stages of malaria parasites. Monoclonal and polyclonal antibodies directed against the C-terminal 42-kDa fragment inhibited the invasion of erythrocytes by P. falciparum merozoites (5, 7). Recombinant MSP-119 of Plasmodium yoelii, P. falciparum, and Plasmodium cynomolgi resulted in protection in mice (P. yoelii) and in monkeys (P. falciparum and P. cynomolgi) (6, 36, 33). The presence of antibodies against P. falciparum MSP-1 (PfMSP-1) correlates with the development of clinical immunity against P. falciparum malaria (17). MSP-1-mediated protective immune responses have been shown to be largely antibody dependent, with high antibody titers being essential for protection (11).
Plasmodium vivax is the second most prevalent human malaria parasite; it is present mostly in South America, Asia, and Oceania (28). P. vivax merozoites express a surface protein equivalent to PfMSP-1, referred as PvMSP-1. Relatively little is known about PvMSP-1 with respect to its processing, the fate of putative processing fragments, and protective immune responses (9). However, two monkey immunization studies with recombinant PvMSP-1- and P. cynomolgi MSP-1 (PcMSP-1)-based antigens have highlighted the protective potential of these antigens. Rhesus monkeys immunized with baculovirus-expressed PcMSP-119 or PcMSP-142 in Freund's adjuvant were protected against the homologous challenge (33), and Saimiri monkeys immunized with a PvMSP-119-based immunogen were partially protected (39).
In contrast to the large number of studies that have been performed with PfMSP-1 (26) and P. yoelii MSP-1 (PyMSP-1) (12), relatively little is known about the immunogenicities of PvMSP-142 and PvMSP-119 formulated in different adjuvant systems (40), although immunization studies with these antigens expressed in baculovirus (31) or in yeast cells (39) have been reported. We describe here the expression and purification of both PvMSP-142 and PvMSP-119 from Escherichia coli and the immune responses in mice against these two antigens in six different adjuvant formulations. We found that both PvMSP-119 and PvMSP-142 were immunogenic in most adjuvant formulations, including alum, and that, although immunization with PvMSP-142 produced PvMSP-119-specific antibodies, a significant portion of the immune response was focused on the rest of the structure.
TL;DR: Analysis of Anopheles species collected from 11 provinces within four departments in eastern Peru during 2001 and 2002 for infections with P. falciparum and P. vivax suggests An.
Abstract: Malaria, both Plasmodium falciparum (Welch) and Plasmodium vivax (Grassi & Feletti), has reemerged as a significant public health disease issue in Peru, especially in forested areas in the eastern part of the country. The spread of Anopheles darlingi Root, the principal South American malaria vector, into new areas of Peru is thought to be a factor in this resurgence. However, epidemiological evidence suggests that in malaria endemic areas of eastern Peru where An. darlingi does not occur, other species are involved in malaria transmission. The objective of this study was to analyze Anopheles species collected from 11 provinces within four departments in eastern Peru during 2001 and 2002 for infections with P. falciparum and P. vivax. More than 84,000 Anopheles mosquitoes representing 13 species were tested by enzyme-linked immunosorbent assay for the presence of Plasmodium circumsporozoite (CS) proteins. Of these, only An. darlingi and Anopheles benarrochi Gabaldon, Cova Garcia & Lopez were found positive. In total, 14 (0.98%) of 1,432 pools of An. darlingi were positive for Plasmodium species; specifically 10 (0.70%) pools were positive for P. falciparum, two (0.14%) were positive for P. vivax VK210, and two (0.14%) were positive for P. vivax VK247 proteins. Nine (0.14%) of 6,323 pools of An. benarrochi were positive for Plasmodium; five (0.08%) of 6,323 pools were positive for P. falciparum, two (0.03%) were positive for P. vivax VK247, one (0.02%) was positive for mixed P. vivax VK210/VK247 infections, and one (0.02%) was positive for mixed P. falciparum and P. vivax VK210 CS-proteins. Although infection rates in An. benarrochi were significantly lower (0.14%) than rates found for An. darlingi (0.98%), our data suggest that An. benarrochi may play a role in transmitting and maintaining Plasmodium species in various malaria endemic areas of eastern Peru.
TL;DR: The results suggest that recombinant PvRII formulated with human compatible adjuvants is immunogenic in small animal models and that Montanide ISA720, AS02A and alum perform better than MF59 and QS21 in terms of their ability to elicit high titer binding inhibitory antibodies.
TL;DR: The susceptibility of 20 isolates of Plasmodium vivax on the Thailand-Myanmar border to seven antimalarial drugs was evaluated using the schizont maturation inhibition technique, finding that P. v Vivax was more sensitive to chloroquine and artesunate, equally sensitive to quinine, and more resistant to mefloquine.
Abstract: The susceptibility of 20 isolates of Plasmodium vivax on the Thailand-Myanmar border to seven antima- larial drugs was evaluated using the schizont maturation inhibition technique. The geometric mean 50% inhibition concentration (IC50) values were quinine 308 ng/mL, amodiaquine 14 ng/mL, chloroquine 50 ng/mL, mefloquine 127 ng/mL, sulfadoxine/pyrimethamine (80:1) 800/10 ng/mL, pyrimethamine 8 ng/mL, and artesunate 0.5 ng/mL. Compared with P. falciparum in this area, P. vivax was more sensitive to chloroquine and artesunate, equally sensitive to quinine, and more resistant to mefloquine.
TL;DR: An outbreak of Plasmodium vivax malaria in Far North Queensland in 2002 is described to describe an outbreak of the disease.
Abstract: Objective: To describe an outbreak of Plasmodium vivax malaria in Far North Queensland in 2002. Design: Epidemiological and entomological investigations; molecular analyses of the infecting parasites. Main outcome measures: Case characteristics, adult and larval mosquito counts at the outbreak location, haplotyping of parasites in blood samples from different cases determined through sequencing of AMA1 and MSP1 genes. Results: A man with imported P. vivax malaria stayed at a camping ground 95 km north of Cairns in late September 2002. This led to an outbreak of P. vivax malaria in 10 adults who stayed at the camping ground in October. Large numbers of Anopheles farauti sensu lato larvae were present in stagnant pools in a creek at the camping ground, and many adult mosquitoes were collected nearby. Not only had most of the infected patients been exposed to mosquitoes at night, they were also less likely than other campers to have used insect repellents appropriately (odds ratio, 0.01; P < 0.001). Two different haplotypes of P. vivax, only one of which was detected in the imported case, were involved in the outbreak. Conclusions: Although local transmission of malaria is rare in Far North Queensland, the risk is probably higher in the dry season (September to December). Campers need to be aware of the increased risk of mosquito-borne diseases. Sexual recombination of multiple gametocytes in mosquitoes infected by the imported case may have resulted
TL;DR: A preliminary cross sectional descriptive study suggests that the mechanism of resistance/susceptibility to infection and/or malaria pathogenesis in pregnant women may differ according to Plasmodium species and that the extensively described increase in the frequencies of malaria infection during pregnancy may be specifically due to P. falciparum infection.
Abstract: Malaria remains globally the most important parasitic disease of man. Data on its deleterious effects during pregnancy have been extensively documented in hyperendemic, holoendemic, and mesoendemic areas from Africa and Asia where Plasmodium falciparum is responsible for almost all infections. However, knowledge about malaria during pregnancy in areas where transmission is unstable and P. vivax is the most prevalent species, such as the Brazilian Amazon, is scarce. Here, we report a preliminary cross sectional descriptive study, carried out at the Fundacao de Medicina Tropical do Amazonas, a reference centre for diagnosis and treatment of tropical diseases in the west-Amazon (Manaus, Brazil). A total of 1699 febrile childbearing age women had positive thick blood smears to Plasmodium species, between January and November 1997: 1401 (82.5%) were positive for P. vivax, 286 (16.8%) for P. falciparum and 12 (0.07%) carried mixed infections. From the malarious patients, 195 were pregnant. The ratio of P. falciparum to P. vivax infections in the group of non-pregnant infected women was 1:5.6 while it was 1:2.3 in that of pregnant infected ones. Similar rates or even proportionally more vivax infections during pregnancy were expected to occur, in function of the contraindication of primaquine with the resulting increased P. vivax relapse rates. Such an observation suggests that the mechanism of resistance/susceptibility to infection and/or malaria pathogenesis in pregnant women may differ according to Plasmodium species and that the extensively described increase in the frequencies of malaria infection during pregnancy may be specifically due to P. falciparum infection.