Social Sciences and Malaria

EHP Library Malaria Bulletin No. 18: July 31-Aug 9, 2001

Trans R Soc Trop Med Hyg 2001 May-Jun;95(3):233-8

Vector-borne infections in the tropics and health policy issues in the twenty-first century.

Molyneux DH.

Liverpool School of Tropical Medicine, Pembroke Place, Liverpool L3 5QA, UK.

Over the past 2 decades scientific advances and evolving strategies have significantly contributed to improved tools for control of vector-borne infections. These are: diagnostics–rapid assessment methods, non-invasive or minimally so yet sensitive and specific; new chemotherapeutics; pyrethroid insecticides and biological insecticidal products; refined strategies, such as combination therapy, rotation of insecticides for resistance management, community-directed treatment, standardized monitoring and evaluation to define programme progress; better epidemiological knowledge through improved identification of parasites and vectors; GIS, remote sensing and climate models which provide tools for epidemic prediction, planning control programmes and permit effective policy analysis; greater involvement of NGDOs (non-governmental development organizations) and CSOs (civil society organizations) in control; advent of donation programmes which involve community-based or directed mass drug distribution. Future problems could be: (1) the over-emphasis on inflexible financing by the insistence of donors on SWAps (sector-wide investment), (2) the over-reliance on pyrethroid pesticides, (3) the over-expectation that basic research will provide new drugs and vaccines for resource-poor settings in the necessary time scales, and (4) the failure to recognize that biological processes have an inherent capacity for change which outstrips the capacity of health services to respond. Malaria is a paradigm of an ’emerging disease’. (5) The challenge of implementing a ‘vertical’ approach to disease control within national health programmes, in the face of significant donor opposition to such programmes is a challenge even when such approaches will secure a ‘public good’.

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Niger Postgrad Med J 2001 Mar;8(1):1-6

Knowledge and Management of Malaria in under Five Children by Primary Health Care Workers in Ibadan South-East Local Government Area.

Fawole OI, Onadeko MO.

Department of Preventive and Social Medicine, College Of Medicine, University of Ibadan, lbadan, Nigeria.

The results of a survey of the knowledge and management practices of 61 health workers in five primary health care facilities in Ibadan South-east LGA are presented. In addition, 30 health workers were observed as they managed children with fever and the parasite status of 92 children diagnosed to have malaria was determined. Results revealed that 62(67.4%) children had the malaria parasite. Knowledge of some basic concepts was fairly adequate as the majority 46(75.401o) knew the cause of malaria. Treatment practices were poor as only 34(55.7010) and 39(63.9%) health workers respectively prescribed chloroquine and paracetamol correctly. Observation revealed that history taking and physical examinations were rudimentary. Scores out of 100 on correct prescriptions of chloroquine and paracetamol were 60.1 and 76.8 respectively. There is an urgent need for periodic education programmes, especially for health workers with many years of experience to help them maintain clinical skills and refresh their knowledge.

PubMed

J Infect Dis 2001 Sep 1;184(5):627-32The influence of placental malaria infection and maternal hypergammaglobulinemia on transplacental transfer of antibodies and igg subclasses in a rural west african population.

Okoko BJ, Wesumperuma LH, Ota MO, Pinder M, Banya W, Gomez SF, McAdam KP, Hart AC.

Vaccine Trial Unit, Medical Research Council, Fajara, Banjul, The Gambia, West Africa.
[email protected]

Two hundred thirteen mother-baby pairs in The Gambia were studied to determine the influence of placental malaria infection and maternal hypergammaglobulinemia on transplacental antibody transfer. Antibody transfer for herpes simplex virus 1 (HSV-1), respiratory syncytial virus (RSV), and varicella-zoster virus (VZV) was significantly reduced by placental malaria infection by 69%, 58%, and 55%, respectively. Maternal hypergammaglobulinemia was associated with a significant reduction in antibody transfer for HSV-1, RSV, VZV, and pneumococcus by 89%, 90%, 91%, and 88%, respectively. In addition, placental malaria infection was associated with a significant reduction in transfer of IgG1, IgG2, and IgG4 (P<.01, P=.01, and P=.03, respectively) but not of IgG3 (P=.59). Maternal hypergammaglobulinemia significantly impaired the transfer of IgG1 and IgG2 (P=.01) but not of IgG3 or IgG4 (P=.62 and P=.59, respectively). Placental malaria infection and maternal hypergammaglobulinemia were associated with reduction in the transplacental transfer of these specific antibodies, IgG1, and IgG2 in this Gambian population.

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J Infect Dis 2001 Sep 1;184(5):618-26

Acquisition and Decay of Antibodies to Pregnancy-Associated Variant Antigens on the Surface of Plasmodium falciparum-Infected Erythrocytes That Protect against Placental Parasitemia.

Staalsoe T, Megnekou R, Fievet N, Ricke CH, Zornig HD, Leke R, Taylor DW, Deloron P, Hviid L.

Centre for Medical Parasitology, Copenhagen University Hospital (Rigshospitalet) and Institute for Medical Microbiology and Immunology, University of Copenhagen, 2200 Copenhagen N, Denmark.
[email protected]

Otherwise clinically immune women in areas endemic for malaria are highly susceptible to Plasmodium falciparum malaria during their first pregnancy. Pregnancy-associated malaria (PAM) is characterized by placental accumulation of infected erythrocytes that adhere to chondroitin sulfate A (CSA). Susceptibility to PAM decreases with increasing parity, apparently due to acquisition of antibodies directed against the variant surface antigens (VSAs) that mediate the adhesion to CSA (VSA(CSA)). This study found that levels of VSA(CSA)-specific antibodies depend on endemicity, that anti-VSA(CSA) IgG is acquired during gestation week 20, and that plasma levels of the antibodies decline during the postpartum period. There is evidence that VSA(CSA)-specific antibodies are linked to placental infection and that high antibody levels contribute to the control of placental infection by inhibiting parasite adhesion to CSA. Data suggest that VSA(CSA) is a target for vaccination against PAM.

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 Proc Natl Acad Sci U S A 2001 Aug 7 [epub ahead of print]

Exploring the transcriptome of the malaria sporozoite stage.

Kappe SH, Gardner MJ, Brown SM, Ross J, Matuschewski K, Ribeiro JM, Adams JH, Quackenbush J, Cho J, Carucci DJ, Hoffman SL, Nussenzweig V.

Michael Heidelberger Division, Department of Pathology, Kaplan Cancer Center, New York University School of Medicine, New York, NY 10016; The Institute for Genomic Research, 9712 Medical Center Drive, Rockville, MD 20850; Research Computing Resource, New York University Medical Center, New York, NY 10016; Medical Entomology Section, Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892-0425; Department of Biological Sciences, University of Notre Dame, Notre Dame, IN 46556; Malaria Program, Naval Medical Research Center, Silver Spring, MD 20910; and Celera Genomics, 45 West Gude Drive, Rockville, MD 20850.

Most studies of gene expression in Plasmodium have been concerned with asexual and/or sexual erythrocytic stages. Identification and cloning of genes expressed in the preerythrocytic stages lag far behind. We have constructed a high quality cDNA library of the Plasmodium sporozoite stage by using the rodent malaria parasite P. yoelii, an important model for malaria vaccine development. The technical obstacles associated with limited amounts of RNA material were overcome by PCR-amplifying the transcriptome before cloning. Contamination with mosquito RNA was negligible. Generation of 1,972 expressed sequence tags (EST) resulted in a total of 1,547 unique sequences, allowing insight into sporozoite gene expression. The circumsporozoite protein (CS) and the sporozoite surface protein 2 (SSP2) are well represented in the data set. A blastx search with all tags of the nonredundant protein database gave only 161 unique significant matches (P(N) </= 10(-4)), whereas 1,386 of the unique sequences represented novel sporozoite-expressed genes. We identified ESTs for three proteins that may be involved in host cell invasion and documented their expression in sporozoites. These data should facilitate our understanding of the preerythrocytic Plasmodium life cycle stages and the development of preerythrocytic vaccines.

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Braz J Infect Dis 2001 Apr;5(2):67-72

Atovaquone and Proguani Hydrochloride Compared with Chloroquine or Pyrimethamine/Sulfodaxine for Treatment of Acute Plasmodium falciparum Malaria in Peru.

Llanos-Cuentas A, Campos P, Clendenes M, Canfield J, Hutchinson DB.

Alexander von Humboldt Tropical Medicine Institute, Universidad Peruana Cayetano Heredia, Lima, Peru.

The efficacy and safety of a fixed-dose combination of atovaquone and proguanil hydrochloride (Malarone(TM)) were compared with chloroquine or pyrimethamine/sulfadoxine in patients with acute falciparum malaria in northern Peru. Patients were initially randomized to receive 1,000 mg atovaquone and 400 mg proguanil hydrochloride daily for 3 days (n=15) or 1,500 mg chloroquine (base) over a 3 day period (n=14) (phase 1). The cure rate with chloroquine was lower than expected and patients were subsequently randomized to receive a single dose of 75 mg pyrimethamine and 1,500 mg sulfadoxine (n=9) or atovaquone/proguanil as before (n=5) (phase 2). In phase 1, atovaquone/proguanil was significantly more effective than chloroquine (cure rate 100% [14/14] vs. 8% [1/13], P<0.0001). In phase 2, atovaquone/proguanil and pyrimethamine/sulfadoxine were both highly effective (cure rates 100% [5/5] and 100% [7/7]). There were no significant differences between treatment groups in parasite or fever clearance times. Adverse events were typical of malarial symptoms and did not differ significantly between groups. Overall efficacy of atovaquone/proguanil was 100% for treatment of acute falciparum malaria in a region with a high prevalence of chloroquine resistance.

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Trans R Soc Trop Med Hyg 2001 May-Jun;95(3):320-4

Compliance to correct dose of chloroquine in uncomplicated malaria correlates with improvement in the condition of rural Nigerian children.

Okonkwo PO, Akpala CO, Okafor HU, Mbah AU, Nwaiwu O.

Department of Pharmacology and Therapeutics, University of Nigeria Teaching Hospital, PMB 01129, Enugu, Nigeria. [email protected]

Non-compliance to correct dosing is thought to be one of the main causes of treatment failure of chloroquine in the home management of childhood malaria. There are few studies of compliance to drugs used for tropical diseases. In order to study compliance in the rural setting, chloroquine syrup was packaged with a novel pictorial insert for compliance to correct dosing. Compliance was assessed in a field trial in September 1996-December 1997, involving 632 children with uncomplicated malaria in Udi local government area in Nigeria. Written informed consent was obtained from mothers/guardians before children were enrolled in the study. There were 3 arms to the trial: control villages (group I) received chloroquine syrup without further intervention, group II received a pictorial insert with chloroquine syrup, and group III received chloroquine syrup, the pictorial insert and verbal instructions. Each group was made up of 3 health centres. Compliance was assessed by volumetric measurement of the chloroquine syrup left in 30-mL bottles and by questionnaires administered to mothers/helpers of the children. Control villages recorded full compliance for 36.5 +/- 4.4% of the children, group II for 51.9 +/- 7.9% and group III for 73.3 +/- 4.2%. There was a significant correlation (P < 0.0001) between full compliance, improvement and time for improvement of the condition. This study is deemed important because it focuses on children, who bear the greatest burden of malaria. It is unique for introducing a pictorial insert that illiterate villagers, who may not understand the use of age or weight in drug dispensing, may utilize as a substitute.

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Trans R Soc Trop Med Hyg 2001 May-Jun;95(3):315-9

Can pretreatment screening for dhps and dhfr point mutations in Plasmodium falciparum infections be used to predict sulfadoxine-pyrimethamine treatment failure?

Omar SA, Adagu IS, Warhurst DC.

Biomedical Sciences Research Centre, Kenya Medical Research Institute, P.O. Box 54840, Mbagathi Road, Nairobi, Kenya.

This study examines the relationship between malaria treatment failure after sulfadoxine-pyrimethamine (S-P) chemotherapy and presence of mutations in the Plasmodium falciparum dihydropteroate synthase (dhps) and dihydrofolate reductase (dhfr) genes (associated with resistance in vitro to S and P) before treatment. In Kenya, 38 malaria patients in a holoendemic area, and 21 in an epidemic area, participated in the trial in 1997-98. In the 2 areas, drug failure occurred in 76% and 75% of cases where any mutation in dhfr was seen (positive predictive values 76% and 75%: P = 0.003 and 0.008) and an identical association was seen with dhfr Asn-108. In the holoendemic area all occurrences of > or = 2 mutations in dhfr predicted drug failure. Only 3 instances were seen in the epidemic focus, but treatment failed in all. Only in the epidemic focus, 7 (88%) of 8 occurrences of > or = 1 mutations in dhps, and all occurrences of the Gly-437 allele of dhps, predicted failure. Association between mutations in dhps and mutations in dhfr was noted in the combined sites, irrespective of outcome. Although this makes the relationship of combined dhfr and dhps mutations to failure more difficult to interpret, it nevertheless supports S-P selection acting on both genes. In the holoendemic site, treatment success increased with age. In this location, acquired immunity may mask the impact of mutations in dhps, since sulfadoxine is a less effective treatment than pyrimethamine.

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Trans R Soc Trop Med Hyg 2001 May-Jun;95(3):267-9

Validity of Lot Quality Assurance Sampling to optimize falciparum malaria surveys in low-transmission areas.

Rabarijaona L, Rakotomanana F, Ranaivo L, Raharimalala L, Modiano D, Boisier P, De Giorgi F, Raveloson N, Jambou R.

Pasteur Institute of Madagascar, University of Rome, Italy.

To control the reappearance of malaria in the Madagascan highlands, indoor house-spraying of DDT was conducted from 1993 until 1998. Before the end of the insecticide-spraying programme, a surveillance system was set up to allow rapid identification of new malaria epidemics. When the number of suspected clinical malaria cases notified to the surveillance system exceeds a predetermined threshold, a parasitological survey is carried out in the community to confirm whether or not transmission of falciparum malaria is increasing. Owing to the low specificity of the surveillance system, this confirmation stage is essential to guide the activities of the control programme. For this purpose, Lot Quality Assurance Sampling (LQAS), which usually requires smaller sample sizes, seemed to be a valuable alternative to conventional survey methods. In parallel to a conventional study of Plasmodium falciparum prevalence carried out in 1998, we investigated the ability of LQAS to rapidly classify zones according to a predetermined prevalence level. Two prevalence thresholds (5% and 15%) were tested using various sampling plans. A plan (36, 2), meaning that at least 2 individuals found to be positive among a random sample of 36, enabled us to classify a community correctly with a sensitivity of 100% and a specificity of 94%. LQAS is an effective tool for rapid assessment of falciparum malaria prevalence when monitoring malaria transmission.

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Parasite Immunol 2001 Aug;23(8):435-44

Immunogenicity of recombinant fragments of Plasmodium falciparum acidic basic repeat antigen produced in Escherichia coli.

Kushwaha A, Rao PP, Suresh Rp, Chauhan VS.

International Centre for Genetic Engineering and Biotechnology, Aruna Asaf Ali Marg, New Delhi, India.

The acidic basic repeat antigen (ABRA) of Plasmodium falciparum is a potential vaccine candidate against erythrocytic stages of malaria. We report, for the first time, the immunological characteristics of recombinant ABRA constructs. The recombinant proteins representing different fragments of ABRA were expressed in Escherichia coli, either as fusions with maltose binding protein or as 6X histidine tagged molecules, and purified by affinity chromatography. Immunogenicity studies with these constructs in rabbits and mice indicated that the N-terminal region is the least immunogenic part of ABRA. T-cell proliferation experiments in mice immunized with these constructs revealed that the T-cell epitopes were localized in the middle portion of the protein. More importantly, the purified immunoglobulin G specific to middle and C-terminal fragments prevented parasite growth at levels approaching 80-90%. We found that these proteins were also recognized by sera from P. falciparum-infected patients from Rourkela, a malaria endemic zone of India. Our immunogenicity results suggest that potential of ABRA as a vaccine candidate antigen should be investigated further.

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Ann Trop Med Parasitol 2001 Jul;95(5):445-9

Apparent drug failure following artesunate treatment of Plasmodium falciparum malaria in Freetown, Sierra Leone: four case reports.

Sahr F, Willoughby VR, Gbakima AA, Bockarie MJ.

College of Medicine and Allied Health Sciences, University of Sierra Leone, Private Mail Bag, Freetown, Sierra Leone.

Four cases of Plasmodium falciparum malaria who presented in Sierra Leone in November-December 2000 apparently failed to respond to treatment with artesunate. Three (75%) of the cases fulfilled the World Health Organization’s criteria for late treatment failure. Although artesunate ranks only sixth as the first-line drug used by clinicians for the treatment of uncomplicated malaria in Sierra Leone, it is widely sold over the counter in pharmacies in the country. The indiscriminate and injudicious use of artesunate among the Sierra Leonean population is likely to increase the level and frequency of resistance among the local strains of P. falciparum. It is recommended that artesunate be reserved for patients who fail to respond to treatment with another of the antimalarial drugs available. Even then, the artesunate should preferably be used in combination with other, longer-acting antimalarial drugs, to slow the development of further resistance.

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Ann Trop Med Parasitol 2001 Jul;95(5):437-444

Malaria diagnosis and treatment under the strategy of the integrated management of childhood illness (IMCI): relevance of laboratory support from the rapid immunochromatographic tests of ICT Malaria P.f/P.v and OptiMal.

Tarimo DS, Minjas JN, Bygbjerg IC.

Department of Parasitology and Medical Entomology, Institute of Public Health, Muhimbili University College of Health Sciences, University of Dar es Salaam, P.O. Box 65001, Dar es Salaam, Tanzania, and Department of International Health, Institute of Public Health, University of Copenhagen, Panum Institute, Blegdamsvej 3, DK-2200 Copenhagen N, Denmark.

The algorithm developed for the integrated management of childhood illness (IMCI) provides guidelines for the treatment of paediatric malaria. In areas where malaria is endemic, for example, the IMCI strategy may indicate that children who present with fever, a recent history of fever and/or pallor should receive antimalarial chemotherapy. In many holo-endemic areas, it is unclear whether laboratory tests to confirm that such signs are the result of malaria would be very relevant or useful. Children from a holo-endemic region of Tanzania were therefore checked for malarial parasites by microscopy and by using two rapid immunochromatographic tests (RIT) for the diagnosis of malaria (ICT Malaria P.f/P.v and OptiMal((R))). At the time they were tested, each of these children had been targeted for antimalarial treatment (following the IMCI strategy) because of fever and/or pallor. Only 70% of the 395 children classified to receive antimalarial drugs by the IMCI algorithm had malarial parasitaemias (68.4% had Plasmodium falciparum trophozoites, 1.3% only P. falciparum gametocytes, 0.3% P. ovale and 0.3% P. malariae). As indicators of P. falciparum trophozoites in the peripheral blood, fever had a sensitivity of 93.0% and a specificity of 15.5% whereas pallor had a sensitivity of 72.2% and a specificity of 50.8%. The RIT both had very high corresponding sensitivities (of 100.0% for the ICT and 94.0% for OptiMal) but the specificity of the ICT (74.0%) was significantly lower than that for OptiMal (100.0%). Fever and pallor were significantly associated with the P. falciparum asexual parasitaemias that equalled or exceeded the threshold intensity (2000/&mgr;l) that has the optimum sensitivity and specificity for the definition of a malarial episode. Diagnostic likelihood ratios (DLR) showed that a positive result in the OptiMal test (DLR = infinity) was a better indication of malaria than a positive result in the ICT (DLR = 3.85). In fact, OptiMal had diagnostic reliability (0.93) which approached that of an ideal test and, since it only detects live parasites, OptiMal is superior to the ICT in monitoring therapeutic responses. Although the RIT may seem attractive for use in primary health facilities because relatively inexperienced staff can perform them, the high cost of these tests is prohibitive. In holo-endemic areas, use of RIT or microscopical examination of bloodsmears may only be relevant when malaria needs to be excluded as a cause of illness (e.g. prior to treatment with toxic or expensive drugs, or during malaria epidemics). Wherever the effective drugs for the first-line treatment of malaria are cheap (e.g. chloroquine and Fansidar), treatment based on clinical diagnosis alone should prove cost-saving in health facilities without microscopy.

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Rev Saude Publica 2001 Jun;35(3):224-31

A mathematical model for malaria transmission relating global warming and local socioeconomic conditions.

Yang HM.

Departamento de Matematica Aplicada, Instituto de Matematica, Estatistica e Computacao Cientifica, Universidade Estadual de Campinas, Campinas, SP, Brasil.

OBJECTIVE: Sensitivity analysis was applied to a mathematical model describing malaria transmission relating global warming and local socioeconomic conditions. METHODS: A previous compartment model was proposed to describe the overall transmission of malaria. This model was built up on several parameters and the prevalence of malaria in a community was characterized by the values assigned to them. To assess the control efforts, the model parameters can vary on broad intervals. RESULTS: By performing the sensitivity analysis on equilibrium points, which represent the level of malaria infection in a community, the different possible scenarios are obtained when the parameters are changed. CONCLUSIONS: Depending on malaria risk, the efforts to control its transmission can be guided by a subset of parameters used in the mathematical model.

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Southeast Asian J Trop Med Public Health 2001 Mar;32(1):83-7

Preliminary studies of Anopheles mosquitos in eight provinces in Lao PDR.

Vythilingam I, Keokenchan K, Phommakot S, Nambanya S, Inthakone S.

Institute for Medical Research, Jalan Pahang, Kuala Lumpur, Malaysia.

Malaria vector surveys were carried out in 8 provinces in Lao PDR in 1999. The surveys were conducted in 4 provinces – Savannakhet, Champasak, Luang Perbang and Sayaboury in May and in another 4 provinces – Bolikhamsay, Sarvan, Sekong and Vientiane in December 1999. Bare leg collection were carried out indoors and outdoors from 6 pm to 5 am. All anopheline mosquitos were identified, dissected and the gut, gland and ovaries were examined. A total of 438 Anopheles mosquitos belonging to 19 species were obtained. Of these only 3 species were found to be infected with oocysts – An. maculatus, An. dirus and An. minimus. All these species were found biting both indoors and outdoors. An. aconitus was the predominant species obtained in the December collection but its vectorial status remains unknown.

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Southeast Asian J Trop Med Public Health 2001 Mar;32(1):57-63

Can treatment of P. vivax lead to a unexpected appearance of falciparum malaria?

Mason DP, Krudsood S, Wilairatana P, Viriyavejakul P, Silachamroon U, Chokejindachai W, Singhasivanon P, Supavej S, McKenzie FE, Looareesuwan S.

Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand. [email protected]

Of 994 patients admitted to the Bangkok Hospital for Tropical Diseases for P. vivax malaria, 104 (10.5%) experienced appearance of Plasmodiumfalciparum following drug treatment for P. vivax . In all patients, P. falciparum parasites were not found by microscopic examination upon admission. The mean time for P. falciparum appearance was 12.6 days after the commencement of chloroquine treatment. Patients experiencing appearance of P. falciparum had significantly lower hematocrit, and greater initial P. vivax parasite counts. We use a mathematical model to explore the consequences of chloroquine treatment of such mixed infections. Both clinical results and features of the model suggest that such “hidden infections” may be quite common, and that the appearance of P. falciparum may be stimulated by treatment of P. vivax.

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Southeast Asian J Trop Med Public Health 2001 Mar;32(1):50-6

Frequency of early rising parasitemia in falciparum malaria treated with artemisinin derivatives.

Silachamroon U, Phumratanaprapin W, Krudsood S, Treeprasertsuk S, Budsaratid V, Pornpininworakij K, Wilairatan P, Looareesuwan S.

Department of Clinical Tropical Medicine, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand. 
[email protected]

To define the frequency of the early rising of parasitemia in falciparum malaria patients treated with artemisinin derivatives, a retrospective chart review of 497 patients admitted to the Hospital for Tropical Diseases, Bangkok in 1996 was carried out. Early rising parasitemia, defined as an increase in the parasite count over the baseline pretreatment level during the first 24 hours of treatment, was found in 59/229 episodes (25.8%) of uncomplicated, and 111/268 episodes (41.3%) of complicated falciparum malaria. All uncomplicated cases were successfully treated without developing any complications. There were 2 deaths and 13 changes of drug regimen in the complicated group. Only one of these unfavorable responses was due to parasite response. Early rising parasitemia was very common in falciparum malaria treated with artemisinin derivatives, despite their ability to clear the parasitemia, and did not indicate failure of the drug used.

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Southeast Asian J Trop Med Public Health 2001 Mar;32(1):41-9

Drug resistant malaria on the Thai-Myanmar and Thai-Cambodian borders.

Wongsrichanalai C, Sirichaisinthop J, Karwacki JJ, Congpuong K, Miller RS, Pang L, Thimasarn K.

Armed Forces Research Institute of Medical Sciences (AFRIMS), Bangkok, Thailand. 
[email protected]

We describe the changing epidemiology of drug resistant malaria in Thailand over the past decade. Factors determining the characteristic patterns of the development and spread of resistance to anti-malarial drugs on the Thai-Cambodian border and the Thai-Myanmar border are explored, namely, population dynamics, drug usage and malaria control measures. The introduction of artesunate-mefloquine combination in selected areas along the two borders in 1995 is believed to be one of the multiple factors responsible for stabilizing the multidrug resistance problems in Thailand today. Other control measures and inter-governmental co-operation must continue to be strengthened in order to limit the spread of drug resistance malaria in the Southeast Asian region.

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Parasitol Res 2001 Jul;87(7):553-5

Plasmodium falciparum: in vitro growth inhibition by febrile temperatures.

Long HY, Lell B, Dietz K, Kremsner PG.

Department of Parasitology, Institute of Tropical Medicine, University of Tubingen, Germany.

Febrile episodes are the hallmark of malarial infection. We determined the inhibitory effect of febrile temperatures on the in vitro growth of Plasmodium falciparum. Parasites were cultured at various temperatures between 37 degrees C and 40 degrees C for 4 days. A logistic decrease in parasitaemia as a function of temperature was observed for continuous cultures. Incubation of synchronized cultures for different lengths of time during the parasite cycle showed a strong increase of growth inhibition with the maturing of parasites. Febrile temperatures inhibit parasite growth and long, high fevers during malaria may be beneficial for parasite clearance.

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Parasitol Res 2001 Jul;87(7):530-3

Plasmodium falciparum transmission intensity and infection rates in children in Gabon.

Sylla EH, Lell B, Kun JF, Kremsner PG.

Laboratoire de Recherche, Hjpital Albert Schweitzer, Lambarene, Gabon.

Several factors can determine the outcome of a malarial infection. Studies on susceptibility or resistance to malarial infection can be confounded by differences in transmission. In the present study, the relationship between vector abundance and Plasmodium falciparum infection rate of Gabonese children was studied. Indoor human bait catches were conducted in the houses of two groups of children, those who had been found earlier to be either frequently (> 3 infections per year) or rarely (< 0.5 infections per year) infected with P. falciparum. The human biting rate was 12 and 31 bites per person per night during the dry and the rainy season, with 3% and 16% Anopheles, respectively. Anopheles gambiae and A. moucheti were found to be the only vectors involved in the transmission of malaria in this area. No significant difference in the abundance and the rate of P. falciparum infection of the Anopheles mosquitoes was found among children rarely or frequently infected. Differences in transmission cannot account for differences in infection rates in our study group. Hereditary and immunological factors seem to be the primary determinants for the outcome of malarial infection.

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EMBO J 2001 Aug 1;20(15):3975-3983

P25 and P28 proteins of the malaria ookinete surface have multiple and partially redundant functions.

Tomas AM, Margos G, Dimopoulos G, van Lin LH, de Koning-Ward TF, Sinha R, Lupetti P, Beetsma AL, Rodriguez MC, Karras M, Hager A, Mendoza J, Butcher GA, Kafatos F, Janse CJ, Waters AP, Sinden RE.

Leiden University Medical Centre, Laboratory of Parasitology, PO Box 9605, 2300 RC Leiden, The Netherlands, Imperial College of Science, Technology and Medicine, Biology Department, Sir Alexander Fleming Building, Imperial College Road, London SW7 2AZ, UK, European Molecular Biology Laboratory, Meyerhofstrasse 1, 69117 Heidelberg, Germany and Unit of Electron Microscopy and Cryotechniques, Dipartimento Biologia Evolutiva, Universita di Siena, Via P.A. Mattioli 4, 53100 Siena, Italy Corresponding [email protected]

The ookinete surface proteins (P25 and P28) are proven antimalarial transmission-blocking vaccine targets, yet their biological functions are unknown. By using single (Sko) and double gene knock-out (Dko) Plasmodium berghei parasites, we show that P25 and P28 share multiple functions during ookinete/oocyst development. In the midgut of mosquitoes, the formation of ookinetes lacking both proteins (Dko parasites) is significantly inhibited due to decreased protection against lethal factors, including protease attack. In addition, Dko ookinetes have a much reduced capacity to traverse the midgut epithelium and to transform into the oocyst stage. P25 and P28 are partially redundant in these functions, since the efficiency of ookinete/oocyst development is only mildly compromised in parasites lacking either P25 or P28 (Sko parasites) compared with that of Dko parasites. The fact that Sko parasites are efficiently transmitted by the mosquito is a compelling reason for including both target antigens in transmission-blocking vaccines.

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J Ethnopharmacol 2001 Sep;77(1):91-8

A search for natural bioactive compounds in Bolivia through a multidisciplinary approach. Part V. Evaluation of the antimalarial activity of plants used by the Tacana Indians.

Deharo E, Bourdy G, Quenevo C, Munoz V, Ruiz G, Sauvain M.

Institut de Recherche pour le Developpement (IRD), CP 9214, La Paz, Bolivia

One hundred and twenty-five extracts of 122 different plant species traditionally used by the Tacana, a native community living in lowland forest at the base of the last foothills of the Cordillera Oriental of the Bolivian Andes, were screened for antimalarial activity in vitro on Plasmodium falciparum chloroquine resistant (D2) and sensitive strains (F32), and were evaluated in vivo on rodent malaria Plasmodium berghei. Five ethanolic stembark extracts showed marked activity either in vitro or in vivo, and only one of them, Bowdichia virgilioides being traditionally used against malaria, was active in vitro (IC50=1 &mgr;g/ml on both strains) and in vivo (51% at 100 mg/kg). Other active extracts were from Caesalpinia pluviosa bark displaying activity in vitro against chloroquine resistant strain (IC50 8.3 &mgr;g/ml), traditionally used against dysentery; two Lauraceae bark extracts, Nectandra aff. hihua and Licaria canella respectively used for construction purposes and against stomach ache, both displaying activity in vitro against P. falciparum sensible and resistant strains (IC50 around 4 &mgr;g/ml); finally, the bark of a strongly aromatic Burseraceae, Protium glabrescens exuding an anti-inflammatory and analgesic resin, was active in vivo only (61% at 100 mg/kg). Results are discussed in relation with Tacana traditional medicine.

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Vaccine 2001 Aug 14;19(31):4487-95

Plasmodium falciparum circumsporozoite (CS) protein peptides specifically bind to HepG2 cells.

Suarez JE, Urquiza M, Puentes A, Garcia JE, Curtidor H, Ocampo M, Lopez R, Rodriguez LE, Vera R, Cubillos M, Torres MH, Patarroyo ME.

Universidad Nacional de Colombia, Hospital San Juan de Dios, Instituto de Inmunologia, Avda 1 No 10-01, AA 44709, Bogota, Colombia

Hepatocyte invasion by malaria parasites is mediated by specific molecular interactions. Several lines of evidence suggest the importance of the surface plasmodial circumsporozoite (CS) protein in the sporozoite invasion of hepatocytes. Identification of the sequences involved in binding to hepatocytes is an important step towards understanding the structural basis for the sporozoite-hepatocyte interaction. In this study, binding assays between Plasmodium falciparum CS peptides and HepG2 cells were performed. Fifteen overlapping residue 20 mer long peptides, spanning the entire CS sequence, were tested in HepG2 cell binding assays. Five High Binding Activity Peptides (HBAPs) to HepG2 cells were identified: 4593, (NANPNANPNANP); 4383, (&Nmacr;SRSLGEN&Dmacr;DG&Nmacr;NEDNEKLR); 4388, (GNGQGHN&Mmacr;PNDPNRNV&Dmacr;ENA); 4389, (HN&Mmacr;PNDPNRNV&Dmacr;ENANA&Nmacr;SA) and 4390, (DPNRNV&Dmacr;ENANA&Nmacr;SAVKN&Nmacr;N). The HBAP HepG2 interaction is independent of charge and amino-acid composition, but sequence dependent. Four HBAPs (4383, 4388, 4389 and 4390) are bound with similar affinity to a 50 kDa molecule. These HBAPs define three Hepatocyte Binding Sequences (HBSs): HBS-1, located between residues 68 and 87 (HBAP 4383); HBS-11, the repeat NANP region (HBAP 4593), for which anti repeat antibodies are able to specifically inhibit sporozoite invasion of hepatocytes have been reported; and HBS-111, between residues 286 and 315 (HBAPs 4388, 4388 and 4390), respectively. Interestingly, HBS 111 carries two earlier-reported B-epitopes (underlined) in peptides 4388, 4389 and 4390 (GNGQGHNMPNDPNRNVD ENANANSAVKNN) in its sequence. The HBSs reported here show lesser interspecie-variability than the entire protein in species invading the same kind of hepatic cells. This data supports these HBSs’ important role in CS-protein function; they could be used as ligand by the sporozoite to invade hepatic cells.

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Vaccine 2001 Aug 14;19(31):4445-51

Biodegradable PLGA microspheres as a delivery system for malaria synthetic peptide SPf66.

Rosas JE, Hernandez RM, Gascon AR, Igartua M, Guzman F, Patarroyo ME, Pedraz JL.

Pharmacy and Pharmaceutical Technology Laboratory, Pharmacy Faculty, University of the Basque Country (UPV-EHU), Paseo de la Universidad no.7, 01006, Vitoria-Gasteiz, Spain

SPf66 is the first chemically synthesised vaccine to elicit a partial protective immune response against malaria. The aluminium hydroxide (alum)-adsorbed SPf66 vaccine is weakly immunogenic and of poor to moderate efficacy in humans. To investigate the possibility of improving SPf66 vaccine immunogenicity, a delivery system based on poly-D,L-lactide-co-glycolide (PLGA) microspheres was developed and the immune response induced after its subcutaneous administration into mice was evaluated. Microspheres were prepared by a solvent extraction/double emulsion (w/o/w) method and characterised for morphology, size, peptide loading, release profile and peptide integrity. The in vitro and in vivo results obtained showed that there was no apparent effect of the encapsulation procedure on SPf66 integrity and immunogenicity. The subcutaneous administration of microspheres showed a significantly higher immune response (serum IgG levels) than that obtained with alum adsorbed SPf66 and it was comparable to that of SPf66 emulsified with Freund’s adjuvant (FA). These observations illustrate the potential of PLGA microspheres as a delivery system for chemically synthesised antigens.

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J Antimicrob Chemother 2001 Aug;48(2):179-184

Ferrocene-chloroquine analogues as antimalarial agents: in vitro activity of ferrochloroquine against 103 Gabonese isolates of Plasmodium falciparum.

Pradines B, Fusai T, Daries W, Laloge V, Rogier C, Millet P, Panconi E, Kombila M, Parzy D.

Unite de Parasitologie, Institut de Medecine Tropicale du Service de Sante des Armees, Bd C. Livon, Parc Le Pharo, BP 46, 13998 Marseille Armees, France. Service Medical, 6ieme Bataillon d’Infanterie de Marine, Libreville, Gabon. Centre Labusquiere, Universite de Bordeaux II, Bordeaux, France. Institut de Recherche Pierre Fabre, Labege Innopole, France. Departement de Parasitologie-Mycologie-Medecine Tropicale, Faculte de Medecine et des Sciences de la Sante, Libreville, Gabon.

The in vitro activities of ferrochloroquine, chloroquine, quinine, mefloquine, halofantrine, amodiaquine, primaquine, atovaquone and artesunate were evaluated against Plasmodium falciparum isolates from children with uncomplicated malaria from Libreville (Gabon), using an isotopic, micro, drug susceptibility test. The IC(50) values for ferrochloroquine were in the range 0.43-30.9 nM and the geometric mean IC(50) for the 103 isolates was 10.8 nM (95% CI 8.6-13.5 nM), while the geometric means for chloroquine, quinine, mefloquine, amodiaquine and primaquine were 370 nM, 341 nM, 8.3 nM, 18.1 nM and 7.6 &mgr;M, respectively. Ferrochloroquine was active against P. falciparum isolates, 95% of which showed in vitro resistance to chloroquine. Weak positive significant correlations were observed between the responses to ferrochloroquine and that to chloroquine, amodiaquine and quinine, but too low to suggest cross-resistance. There was no significant correlation between the response to ferrochloroquine and those to mefloquine, halofantrine, primaquine, atovaquone or artesunate. Ferrochloroquine may be an important alternative drug for the treatment of chloroquine-resistant malaria.

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J Am Mosq Control Assoc 2001 Jun;17(2):131-6

Concurrent control of mosquitoes and domestic pests by use of deltamethrin-treated curtains in the New Delhi Municipal Committee, India.

Ansari MA, Razdan RK.

Malaria Research Centre, Delhi, India.

A field trial was conducted in Block F of the Moti Bagh area of New Delhi Municipal Committee to demonstrate composite control of Anopheles stephensi and Aedes aegypti by spraying deltamethrin at 100 mg/m2 on window and door curtains of habitations. Results revealed drastic reduction (87.9-93.7%, P < 0.05) of target species in the experimental area. The impact of deltamethrin-treated curtains was also evident against nontarget species (67.9-85.7%. P < 0.05). Treated curtains provided 100% kill of An. stephensi and Ae. aegypti for 3-4 months, followed by a gradual decline in successive months. Use of deltamethrin-treated curtains resulted in 92.0 reduction in slide positivity rate and 95.4% reduction in malaria cases per thousand population. The cost of deltamethrin treatment was Rs 41.15 (<$1 U.S.) per house per annum. Insecticide-treated mosquito window and door curtains, along with legislative measures, may provide cost-effective concurrent control of mosquitoes and other domestic pests.

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Indian J Med Sci 2001 Jan;55(1):43-6

Seasonal variations in incidence of severe and complicated malaria in central India.

Madhavan KT, Jajoo UN, Bhalla A.

Deptt. of Medicine, MGIMS, Sevagram, Wardha.

The geographical position and climate of India is favorable for the transmission of malarial infection. The maximum prevalence of malaria in most parts of India is from July to November months. Rainfall provides mosquitoes, a breeding ground giving rise to epidemics. We studied the seasonal variation in cases of severe and complicated malaria presenting at MGIMS, Sevagram, Wardha (Vidarbha region in Maharashtra) over a period of three years. The findings of peak of malaria observed during September-November during three years period points to the fact that the increase in vector breeding after rainy season is responsible for the upsurge in the malarial cases during these months. This also indicates that this area (Vidarbha) has an unstable transmission of malaria.

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Bull World Health Organ 2001;79(7):648-56

Three case definitions of malaria and their effect on diagnosis, treatment and surveillance in Cox’s Bazar district, Bangladesh.

Montanari RM, Bangali AM, Talukder KR, Baqui A, Maheswary NP, Gosh A, Rahman M, Mahmood AH.

WHO Dhaka, Bangladesh.

In countries where malaria is endemic, routine blood slide examinations remain the major source of data for the public health surveillance system. This approach has become inadequate, however, as the public health emphasis has changed from surveillance of laboratory-confirmed malaria infections to the early detection and treatment of the disease. As a result, it has been advocated that the information collected about malaria be changed radically and should include the monitoring of morbidity and mortality, clinical practice and quality of care. To improve the early diagnosis and prompt treatment (EDPT) of malaria patients, three malaria case definitions (MCDs) were developed, with treatment and reporting guidelines, and used in all static health facilities of Cox’s Bazar district, Bangladesh (population 1.5 million). The three MCDs were: uncomplicated malaria (UM); treatment failure malaria (TFM); and severe malaria (SM). The number of malaria deaths was also reported. This paper reviews the rationale and need for MCDs in malaria control programmes and presents an analysis of the integrated surveillance information collected during the three-year period, 1995-97. The combined analysis of slide-based and clinical data and their related indicators shows that blood slide analysis is no longer used to document fever episodes but to support EDPT, with priority given to SM and TFM patients. Data indicate a decrease in the overall positive predictive value of the three MCDs as malaria prevalence decreases. Hence the data quantify the extent to which the mainly clinical diagnosis of UM leads to over-diagnosis and over-treatment in changing epidemiological conditions. Also the new surveillance data show: a halving in the case fatality rate among SM cases (from 6% to 3.1%) attributable to improved quality of care, and a stable proportion of TFM cases (around 7%) against a defined population denominator. Changes implemented in the EDPT of malaria patients and in the surveillance system were based on existing staff capacity and routine reporting structures.

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J Med Entomol 2001 Jul;38(4):531-6

Effect of permethrin-impregnated nets on exiting behavior, blood feeding success, and time of feeding of malaria mosquitoes (Diptera: Culicidae) in western Kenya.

Mathenge EM, Gimnig JE, Kolczak M, Ombok M, Irungu LW, Hawley WA.

Department of Zoology, University of Nairobi, Kenya.

The impact of permethrin-treated bednets on the feeding and house entering/exiting behavior of malaria vectors was assessed in two studies in western Kenya. In one study, matched pairs of houses were allocated randomly to receive bednets or no bednets. Exiting mosquitoes were collected in Colombian curtains hung around half of each house; indoor resting mosquitoes were collected by pyrethrum spray catches. The number of Anopheles gambiae Giles and An. arabiensis Patton estimated to have entered the houses was unaffected by the presence of bednets; Anopheles funestus Giles was less likely to enter a house if bednets were present. Anopheles gambiae and An. funestus were less likely to obtain a blood meal and significantly more likely to exit houses when bednets were present. No difference was detected in An. arabiensis rates of blood feeding and exiting. In a second experiment, hourly night biting collections were done on 13 nights during the rainy season to assess whether village-wide use of permethrin-treated bednets caused a shift in the time of biting of malaria vectors. A statistically significant shift was detected in the biting times of An. gambiae s.l., although the observed differences were small. No change was observed in the hourly distribution of An. funestus biting. Our study demonstrated that, at least in the short-term, bednets reduced human-vector contact and blood feeding success but did not lead to changes in the biting times of the malaria vectors in western Kenya.

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Curr Drug Targets 2000 Jul;1(1):59-83

Proteases involved in erythrocyte invasion by the malaria parasite: function and potential as chemotherapeutic targets.

Blackman MJ.

Division of Parasitology, National Institute for Medical Research, Ridgeway, Mill Hill, London NW7 1AA, U.K. 
[email protected]

Malaria places an increasing burden on global public health resources. In the face of growing resistance of the malaria parasite to available antimalarial drugs, there is a need for new drugs and the identification of new chemotherapeutic targets. The malaria parasite has a complex life cycle which includes a number of obligate intracellular stages. Clinical malaria results from cyclic asexual replication of the blood-stage parasite in circulating erythrocytes of the human host. Erythrocyte entry and host cell rupture require the activity of parasite proteases, and these enzymes are, therefore, attractive targets for rational approaches to new drug development. Malarial proteases play a role in at least two distinct aspects of host cell invasion; modification of parasite proteins involved in host cell recognition and entry; and restructuring of the host cell itself, during and following invasion, and in order to allow parasite release from the host cell. This review details recent advances in the identification of these proteases, describes current understanding of their activation and functional role, and discusses their potential as targets for protease inhibitor-based drugs.