EHP LIBRARY MALARIA BULLETIN 44 –SEPT 3-15, 2002

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FULL-TEXT REPORTS

EHP Activity Report 112 – Eritrea field studies on efficacy of bacterial larvicides for use in malaria control.
http://www.ehproject.org/PDF/Activity_Reports/AR112-ERVectCntrlStdiesFINAL.pdf

SOCIAL SCIENCES AND MALARIA

Bull World Health Organ 2002;80(8):660-6

Control of malaria: a successful experience from Viet Nam.

Hung le Q, Vries PJ, Giao PT, Nam NV, Binh TQ, Chong MT, Quoc NT, Thanh TN, Hung LN, Kager PA.

Division of Infectious Diseases, Tropical Medicine AIDS, Academic Medical Centre, Amsterdam, Netherlands.

OBJECTIVE: To follow malaria prospectively in an ethnic minority commune in the south of Viet Nam with high malaria transmission and seasonal fluctuation, during malaria control interventions using insecticide-treated bednets (ITBNs) and early diagnosis and treatment (EDT) of symptomatic patients. METHODS: From 1994 onwards the following interventions were used: distribution of ITBNs to all households with biannual reimpregnation; construction of a health post and appointment of staff trained in microscopic diagnosis and treatment of malaria; regular supply of materials and drugs; annual cross-sectional malaria surveys with treatment of all parasitaemic subjects, and a programme of community involvement and health education. Surveys were held yearly at the end of the rainy season. During the surveys, demographic data were updated. Diagnosis and treatment of malaria were free of charge. Plasmodium falciparum infection was treated with artesunate and P. vivax infection with chloroquine plus primaquine. FINDINGS: The baseline survey in 1994 recorded 716inhabitants. Of the children under 2years of age, 37% were parasitaemic; 56% of children aged 2-10 years, and 35% of the remaining population were parasitaemic. P. falciparum accounted for 73-79% of these infections. The respective splenomegaly rates for the above-mentioned age groups were 20%, 56%, and 32%. In 1999, the proportion of parasitaemic subjects was 4%, 7% and 1%, respectively, of which P.falciparum contributed 56%. The splenomegaly rate was 0%, 5% and 2%, respectively. CONCLUSIONS: A combination of ITBNs and EDT, provided free of charge, complemented by annual diagnosis and treatment during malaria surveys and community involvement with health education successfully brought malaria under control. This approach could be applied to other regions in the south of Viet Nam and provides a sound basis for further studies in other areas with different epidemiological patterns of malaria. Bull World Health Organ 2002;80(8):653-9

Cost of malaria control in China: Henan’s consolidation programme from community and government perspectives.

Jackson S, Sleigh AC, Liu XL.

School of Economics, University of Queensland, Queensland, Australia.

OBJECTIVE: To assist with strategic planning for the eradication of malaria in Henan Province, China, which reached the consolidation phase of malaria control in 1992, when only 318 malaria cases were reported. METHODS: We conducted a prospective two-year study of the costs for Henan’s malaria control programme. We used a cost model that could also be applied to other malaria programmes in mainland China, and analysed the cost of the three components of Henan’s malaria programme: suspected malaria case management, vector surveillance, and population blood surveys. Primary cost data were collected from the government, and data on suspected malaria patients were collected in two malaria counties (population 2 093 100). We enlisted the help of 260 village doctors in six townships or former communes (population 247 762), and studied all 12 325 reported cases of suspected malaria in their catchment areas in 1994 and 1995. FINDINGS: The average annual government investment in malaria control was estimated to be US$ 111 516 (case-management 59%; active blood surveys 25%; vector surveillance 12%; and contingencies and special projects 4%). The average cost (direct and indirect) for patients seeking treatment for suspected malaria was US$ 3.48, equivalent to 10 days’ income for rural residents. Each suspected malaria case cost the government an average of US$ 0.78. CONCLUSION: Further cuts in government funding will increase future costs when epidemic malaria returns; investment in malaria control should therefore continue at least at current levels of US$ 0.03 per person at risk. J Health Soc Policy 2002;15(1):59-75

Initiating malaria control programs in the third world: directives for short- and long-term solutions.

Basu S.

Department of Brain and Cognitive Science at MIT, Cambridge, MA 02139, USA.

Although malaria is a growing problem affecting several hundred million people each year, many malarial countries lack successful disease control programs. Worldwide malaria incidence rates are dramatically increasing, generating fear among many people who are witnessing malaria control initiatives fail. In this paper, we explore two options for malaria control in poor countries: (1) the production and distribution of a malaria vaccine and (2) the control of mosquitoes that harbor the malaria parasite. We first demonstrate that the development of a malaria vaccine is indeed likely, although it will take several years to produce because of both biological obstacles and insufficient research support. The distribution of such a vaccine, as suggested by some economists, will require that wealthy states promise a market to pharmaceutical companies who have traditionally failed to investigate diseases affecting the poorest of nations. But prior to the development of a malaria vaccine, we recommend the implementation of vector control pro- grams, such as those using Bti toxin, in regions with low vector capacity. Our analysis indicates that both endogenous programs in malarial regions and molecular approaches to parasite control will provide pragmatic solutions to the malaria problem. But the successful control of malaria will require sustained support from wealthy nations, without whom vaccine development and vector control programs will likely fail. Am J Trop Med Hyg 2002 Jun;66(6):680-5

A cost comparison of two malaria control methods in Kyunggi Province, Republic of Korea, using remote sensing and geographic information systems.

Claborn DM, Masuoka PM, Klein TA, Hooper T, Lee A, Andre RG.

Navy Disease Vector Ecology and Control Center, Naval Air Station, Jacksonville, Florida 32212-0043, USA. Email: [email protected]

A cost-comparison of two methods for the control of malaria in the Republic of Korea was performed. The cost of larviciding with methoprene granules was estimated at $93.48/hectare. The annual cost of providing chemoprophylaxis was estimated at $37.53/person. Remote sensing and geographic information systems were used to obtain estimates of the size of vector larval habitats around two U.S. Army camps, allowing an estimate of the cost of larviciding around each of the camps. This estimate was compared to the cost of providing chloroquine and primaquine chemoprophylaxis for the camp populations. Costs on each of the camps differed by the size of the larval habitats and the size of the at-risk population. These tools allow extrapolation of larval surveillance data to a regional scale while simultaneously providing site-specific cost analysis, thus reducing the cost and labor associated with vector surveillance over large areas.

PUBMED

Clin Infect Dis 2002 Oct 1;35(7):825-33 Randomized, Placebo-Controlled Trial of Atovaquone/Proguanil for the Prevention of Plasmodium falciparum or Plasmodium vivax Malaria among Migrants to Papua, Indonesia.

Ling J, Baird JK, Fryauff DJ, Sismadi P, Bangs MJ, Lacy M, Barcus MJ, Gramzinski R, Maguire JD, Kumusumangsih M, Miller GB, Jones TR, Chulay JD, Hoffman SL.

Naval Medical Research Unit 2, Jakarta, Indonesia; and Children’s National Medical Center and George Washington University, Washington, DC, USA.

The increasing prevalence of resistance to antimalarial drugs reduces options for malaria prophylaxis. Atovaquone/proguanil (Malarone; GlaxoSmithKline) has been >95% effective in preventing Plasmodium falciparum malaria in lifelong residents of areas of holoendemicity, but data from persons without clinical immunity or who are at risk for Plasmodium vivax malaria have not been described. We conducted a randomized, double-blinded study involving 297 people from areas of nonendemicity in Indonesia who migrated to Papua (where malaria is endemic) </=26 months before the study period. Subjects received prophylaxis with 1 Malarone tablet (250 mg of atovaquone and 100 mg of proguanil hydrochloride; n=148) or placebo (n=149) per day for 20 weeks. Hematologic and clinical chemistry values did not change significantly. The protective efficacy of atovaquone/proguanil was 84% (95% confidence interval [CI], 44%-95%) for P. vivax malaria, 96% (95% CI, 72%-99%) for P. falciparum malaria, and 93% (95% CI, 77%-98%) overall. Atovaquone/proguanil was well tolerated, safe, and effective for the prevention of drug-resistant P. vivax and P. falciparum malaria in individuals without prior malaria exposure who migrated to Papua, Indonesia. Infect Immun 2002 Oct;70(10):5857-5859

Requirement for Tumor Necrosis Factor Receptor 2 Expression on Vascular Cells To Induce Experimental Cerebral Malaria.

Stoelcker B, Hehlgans T, Weigl K, Bluethmann H, Grau GE, Mannel DN.

Institute of Pathology/Tumor Immunology, University of Regensburg, 93042 Regensburg, Germany. Pharmaceutical Research Gene Technology, F. Hoffmann-LaRoche Ltd., 4002 Basel, Switzerland. Experimental Parasitology Unit, Faculties of Medicine and Pharmacie, Universite de la Mediterranee, 13385 Marseille, France. Using tumor necrosis factor receptor type 2 (TNFR2)-deficient mice and generating bone marrow chimeras which express TNFR2 on either hematopoietic or nonhematopoietic cells, we demonstrated the requirement for TNFR2 expression on tissue cells to induce lethal cerebral malaria. Thus, TNFR2 on the brain vasculature mediates tumor necrosis factor-induced neurovascular lesions in experimental cerebral malaria. Infect Immun 2002 Oct;70(10):5412-5

Selective Accumulation of Mature Asexual Stages of Plasmodium falciparum-Infected Erythrocytes in the Placenta.

Beeson JG, Amin N, Kanjala M, Rogerson SJ.

Department of Medicine, University of Melbourne, Royal Melbourne Hospital, Victoria 3050, Australia. Malawi-Liverpool-Wellcome Trust Clinical Research Programme, College of Medicine, University of Malawi, Blantyre, Malawi.

A feature of malaria in pregnancy is accumulation of P. falciparum-infected erythrocytes (IEs) in the placenta, which is associated with adverse outcomes for mothers and infants. Infection appears to involve parasite adhesion to molecules such as chondroitin sulfate A, hyaluronic acid, and immunoglobulins. In vitro, adhesion is predominantly a property of mature asexual forms of IEs; however, adhesion of immature or ring forms has recently been reported. We have assessed the parasitemia and developmental stages of IEs in the placenta by examination of placental blood and histological sections with comparison to parasites in the peripheral blood from the same individuals. Approximately 90% of IEs in the placenta were mature forms. Compared to peripheral blood, the placental parasitemia was 10-fold higher and the density of mature IEs was over 200-fold higher. By contrast, the average peripheral and placental ring-stage parasitemias were not significantly different. In 2 of 14 cases, the density of ring forms was higher in placental than in peripheral blood. These findings demonstrate prominent selective accumulation of mature asexual-stage IEs but infrequent accumulation of ring stages in the placental blood spaces, consistent with an important role for mature-stage IE adhesion. Insect Biochem Mol Biol 2002 Oct;32(10):1325

Plasmodium-mosquito interactions, phage display libraries and transgenic mosquitoes impaired for malaria transmission.

Ghosh A, Moreira L, Jacobs-Lorena M.

Department of Genetics, Case Western Reserve University, 10900 Euclid Avenue, 44106-4955, Cleveland, OH, USA.

Malaria continues to kill millions of people every year and new strategies to combat this disease are urgently needed. Recent advances in the study of the mosquito vector and its interactions with the malaria parasite suggest that it may be possible to genetically manipulate the mosquito in order to reduce its vectorial capacity. Here we review the advances made to date in four areas: (1) the introduction of foreign genes into the mosquito germ line; (2) the characterization of tissue-specific promoters; (3) the identification of gene products that block development of the parasite in the mosquito; and (4) the generation of transgenic mosquitoes impaired for malaria transmission. While initial results show great promise, the problem of how to spread the blocking genes through wild mosquito populations remains to be solved. Insect Biochem Mol Biol 2002 Oct;32(10):1317

Engineering mosquito resistance to malaria parasites: the avian malaria model.

James A.

University of California, Irvine, Department of Molecular Biology and Biochemistry, 3205 BioSci II, CA 92697-3900, Irvine, USA.

Genetic approaches to controlling the transmission of mosquito-borne diseases are being developed to augment the available chemical control practices and environmental manipulation methods. Much progress has been made in laboratory-based research that seeks to develop antipathogen or antivector effector genes and methods for genetically manipulating host vector strains. Research is summarized here in the development of a malaria-resistant phenotype using as a model system the avian parasite, Plasmodium gallinaceum, and the mosquito, Aedes aegypti. Robust transformation technology based on a number of transposable elements, the identification of promoter regions derived from endogenous mosquito genes, and the development of single-chain antibodies as effector genes have made it possible to produce malaria-resistant mosquitoes. Future challenges include discovery of methods for spreading antiparasite genes through mosquito populations, determining the threshold levels below which parasite intensities of infection must be held, and defining the circumstances in which a genetic control strategy would be employed in the field. Insect Biochem Mol Biol 2002 Oct;32(10):1311

Implications of Time Bomb model of ookinete invasion of midgut cells.

Han Y, Barillas-Mury C.

Department of Microbiology, Immunology and Pathology, Colorado State University, 300 West Lake Street, CO 80523, Fort Collins, USA.

In this review, we describe the experimental observations that led us to propose the Time Bomb model of ookinete midgut invasion and discuss potential implications of this model when considering malaria transmission-blocking strategies aimed at arresting parasite development within midgut cells. A detailed analysis of the molecular interactions between Anopheles stephensi midgut epithelial cells and Plasmodium berghei parasites, as they migrate through midgut cells, revealed that ookinetes induce nitric oxide synthase (NOS) expression, remodeling of the actin cytoskeleton and characteristic morphological changes in the invaded epithelial cells. Parasites inflict extensive damage that ultimately leads to genome fragmentation and cell death. During their migration through the cytoplasm, ookinetes release a subtilisin-like protease (PbSub2) and the surface protein (Pbs21). The model proposes that ookinetes must escape rapidly from the invaded cells, as the responses mediating cell death could be potentially lethal to the parasites. In other words, the physical and/or chemical damage triggered by the parasite can be thought of as a ‘lethal bomb’. Once this cascade of events is initiated, the parasite must leave the cellular compartment within a limited time to escape unharmed from the ‘bomb’ it has activated. The midgut epithelium has the ability to heal rapidly by ‘budding off’ the damaged cells to the midgut lumen without losing its integrity. Trop Med Int Health 2002 Sep;7(9):744-9

Barriers to prompt and effective treatment of malaria in northern Sri Lanka.

Reilley B, Abeyasinghe R, Pakianathar MV.

Medecins sans Frontieres, Colombo, Sri Lanka, Anti-Malaria Campaign (AMC), Colombo, Sri Lanka.

BACKGROUND For the past 18 years, northern Sri Lanka has been affected by armed ethnic conflict. This has had a heavy impact on displacement of civilians, health delivery services, number of health professionals in the area and infrastructure. The north of Sri Lanka has a severe malaria burden, with less than 5% of the national population suffering 34% of reported cases. Health care providers investigated treatment-seeking behaviour and levels of treatment failure believed to be the result of lack of adherence to treatment. METHODS Pre- and post-treatment interviews with patients seeking treatment in the outpatient department (OPD) and focus groups. RESULTS A total of 271 persons completed interviews: 54.4% sought treatment within 2 days of the onset of symptoms, and 91.9% self-treated with drugs with prior to seeking treatment, mainly with paracetamol. Self-treatment was associated with delaying treatment (RR 3.55, CI 1.23-10.24, P=0.002). In post-treatment interviews, self-reported default was 26.1%. The main reasons for not taking the entire regimen were side-effects (57.6%) and disappearance of symptoms (16.7%). Focus groups indicated some lack of confidence in chloroquine treatment and prophylaxis, and scant enthusiasm for prevention methods. CONCLUSIONS A number of factors contribute to a lack of access and a lower quality of care for malaria: lack of medical staff and facilities because of the fighting; lack of confidence in treatment, and perception of malaria as a routine illness. Prevention efforts need to take into account certain beliefs and practices to be successful. Trop Med Int Health 2002 Sep;7(9):737-743

In vivo drug resistance of falciparum malaria in mining areas of Venezuela.

Ache A, Escorihuela M, Vivas E, Paez E, Miranda L, Matos A, Perez W, Diaz O, Izarra E.

Division de Epidemiologia, Malariologia y Saneamiento Ambiental del Estado Bolivar, Region III, Venezuela Direccion de Endemias Rurales, Ministerio de Salud y Desarrollo Social, Estado Cojedes, Venezuela Centro de Investigaciones ‘Dr Francesco Vitanza’, Estado Bolivar, Venezuela Departamento de Malaria, Direccion de Endemias Rurales, Estado Aragua, Venezuela Instituto de Salud Publica del Estado Bolivar, Estado Bolivar, Venezuela.

The Lot Quality Assurance Double-Sampling Plan (LQADSP) technique was used in three areas, Maripa, Kilometro 88 and Ikabaru, to assess the efficacy of antimalarials used routinely by the VenezuelanMalaria Programme. The use of chloroquine (25 mg/kg), chloroquine (40 mg/kg) and the combination of sulfadoxine (500 mg) and pyrimethamine (25 mg) registered treatment failures above the threshold level of 25% in Maripa and Kilomertro 88. In Ikabaru the use of chloroquine (40 mg/kg) did not surpass that quality level and could possibly be less than 10%. Quinine (30 mg/kg) was totally effective in curing patients in all three areas. The use of this technique seems adequate for rapid field evaluations and in this case for providing appropriate information to assist this health programme. However, whilst being an ideal technique for surveying areas in which considerable variation may exist among lots and particularly for Plasmodium falciparum infections in these areas, repeated surveys should be carried out in the same areas over time to monitor changes in the susceptibility of this parasite to first-, second- and third-line drugs. In that way, national drug policies can be modified adequately. Trop Med Int Health 2002 Sep;7(9):732-6

Malaria control by residual insecticide spraying in Chingola and Chililabombwe, Copperbelt Province, Zambia.

Sharp B, Van Wyk P, Sikasote JB, Banda P, Kleinschmidt I.

Malaria Lead Programme, Medical Research Council, Congella, South Africa Konkola Copper Mines Plc, Chingola, Zambia.

Malaria is endemic in the whole of Zambia and is the leading cause of morbidity and mortality. Prior to 1980, effective malaria control was achieved in the northern mining towns of Chingola and Chililabombwe by means of annual residual spraying programmes. In the 1970s, incidence rates wereaslow as 20/1000 p.a., but by 2000 had increased to 68/1000 p.a. in Chingola and to 158/1000p.a.in Chililabombwe. Konkola Copper Mines (KCM) initiated a malaria control programme in which all dwellings in the two towns and within a 10-km radius were sprayed with either dichlorodiphenyltrichloroethane or a synthetic pyrethroid (Icon by ZENECA or Deltamethrin by Aventis). Houses were sprayed in November and December 2000, at the start of the peak transmission period. There was a statistically significant reduction in malaria incidence recorded at KCM health facilities in the two towns, representing a protective incidence rate ratio of 0.65 (95% CI 0.44, 0.97) when comparing the post-spraying period with the corresponding period of the previous 2 years. This reduction followed a single round of house spraying during a year with higher rainfall than the preceding two and in an area where chloroquine was first-line treatment. This house-spraying programme is an example of private/public sector collaboration in malaria control. Immunol Cell Biol 2002 Oct;80(5):401-14 Immunity to asexual blood stage malaria and vaccine approaches. Wipasa J, Elliott S, Xu H, Good MF. The Cooperative Research Centre for Vaccine Technology, The Queensland Institute of Medical Research, Queensland, Australia, Research Institute for Health Sciences, Chiang Mai University, Chiang Mai, Thailand. The development of a malaria vaccine seems to be a definite possibility despite the fact that even individuals with a life time of endemic exposure do not develop sterile immunity. An effective malaria vaccine would be invaluable in preventing malaria-associated deaths in endemic areas, especially amongst children less than 5 years of age and pregnant women. This review discusses our current understanding of immunity against the asexual blood stage of malaria – the stage that is responsible for the symptoms of the disease – and approaches to the design of an asexual blood stage vaccine. Am J Trop Med Hyg 2002 Jun;66(6):804-11

A cocktail polymerase chain reaction assay to identify members of the Anopheles funestus (Diptera: Culicidae) group.

Koekemoer LL, Kamau L, Hunt RH, Coetzee M.

Department of Clinical Microbiology and Infectious Diseases, School of Pathology of the National Health Laboratory Services and the University of the Witwatersrand, Johannesburg, South Africa. [email protected]

Anopheles funestus Giles is a major malaria vector in Africa belonging to a group of species with morphologically similar characteristics. Morphological identification of members of the A. funestus group is difficult because of overlap of distinguishing characteristics in adult or immature stages as well as the necessity to rear isofemale lines to examine larval and egg characters. A rapid rDNA polymerase chain reaction (PCR) method has been developed to accurately identify five members of the A. funestus group. This PCR is based on species-specific primers in the ITS2 region on the rDNA to identify A. funestus (approximately 505bp), Anopheles vaneedeni Gillies and Coetzee (approximately 587bp), Anopheles rivulorum Leeson (approximately 411bp), Anopheles leesoni Evans (approximately 146bp), and Anopheles parensis Gillies (approximately 252bp). Am J Trop Med Hyg 2002 Jun;66(6):692-9

Nonimmune IgM, but not IgG binds to the surface of Plasmodium falciparum-infected erythrocytes and correlates with rosetting and severe malaria.

Rowe JA, Shafi J, Kai OK, Marsh K, Raza A.

Institute of Cell, Animal and Population Biology, University of Edinburgh, United Kingdom. Email: [email protected]

Recent work suggests that IgG and IgM from nonimmune human serum (natural antibodies) bind to the surface of Plasmodium falciparum-infected erythrocytes and contribute to rosette formation by stabilizing the interaction between infected and uninfected erythrocytes. Here we show, in both laboratory clones and field isolates, that only IgM but not IgG is detected on the surface of infected cells. In field isolates, there was a strong positive correlation between IgM binding and rosette formation (Spearman’s rank correlation coefficient p = 0.804, P < 0.001). Both rosette formation and IgM binding were associated with severe malaria, although statistical analysis indicates that rosette formation is the more strongly associated variable. Rosette formation, but not IgM binding, was also associated with malarial anemia. We conclude that IgM is the predominant class of natural antibodies binding to the surface of infected erythrocytes. However, we could not confirm previous suggestions that infected erythrocytes are coated with nonimmune IgG, which could lead to their interaction with host Fcgamma receptors. Am J Trop Med Hyg 2002 Jun;66(6):686-91

Prognostic value of thrombocytopenia in African children with falciparum malaria.

Gerardin P, Rogier C, Ka AS, Jouvencel P, Brousse V, Imbert P.

Service de Pediatrie, Hjpital Principal, Dakar, Senegal.

Thrombocytopenia is a common finding in malaria, but its prognostic value has not been addressed in children. The relationship between thrombocytopenia (platelet count < 100,000/mm3 on admission) and severity and outcome was investigated prospectively in children hospitalized with falciparum malaria in Dakar, Senegal, an area that is hypoendemic for malaria. Of 288 falciparum cases, 215 matched the 2000 World Health Organization definition of severe malaria. Median platelet counts were lower (98,000/mm3 versus 139,000/mm3; P < 0.02) among severe cases than in mild cases, and in children who died than among those who recovered (68,500/mm3 versus 109,000/mm3; P < 0.002). In severe cases, children presenting with a platelet count < 100,000/mm3 were more likely to die (odds ratio [OR] = 6.31, 95% confidence interval [CI] = 2.0-26.0). Moreover, multivariate analysis identified thrombocytopenia as an independent predictor of death (OR = 13.3, 95% CI = 3.2-55.1). Our data show an association between thrombocytopenia and either severity or prognosis in childhood falciparum malaria. Am J Trop Med Hyg 2002 Jun;66(6):672-9 Anemia in parasite- and recombinant protein-immunized aotus monkeys infected with Plasmodium falciparum. Jones TR, Stroncek DF, Gozalo AS, Obaldia N 3rd, Andersen EM, Lucas C, Narum DL, Magill AJ, Sim BK, Hoffman SL. Malaria Program, Naval Medical Research Center, Silver Spring, Maryland 20910, USA. Plasmodium falciparum-induced anemia was characterized in Aotus monkeys repeatedly immunized by infection with P. falciparum (FVO strain) parasites, then cross-challenged with CAMP strain, or in monkeys receiving blood stage challenges as part of malaria vaccine trials. In 4 studies, 25 (30.5%) of 82 monkeys had at least a 50% reduction in hematocrit; mean day of maximum parasitemia was 12.5, whereas the mean day of minimum hematocrit was 18.8 (P < 0.0009). Decreased hematocrit levels were not associated with reticulocytosis until parasite densities decreased significantly from peak levels. Direct antibody tests to detect IgG and C3d on the surface of erythrocytes were negative. Nonantibody/noncomplement-mediated lysis of uninfected erythrocytes seems to be the principal cause of the anemia, and it also seems that bone marrow suppression and lysis of infected erythrocytes contributed to the anemia. Partial immunity-whether induced by repeated immunization with whole parasites or with vaccine-seems important to the development of anemia. Am J Trop Med Hyg 2002 Jun;66(6):667-71

Molecular epidemiology of malaria in Cameroon. X. Evaluation of PFMDR1 mutations as genetic markers for resistance to amino alcohols and artemisinin derivatives. Basco LK, Ringwald P. Institut de Recherche pour le Developpement and Laboratoire de Recherche sur le Paludisme, Organisation de Coordination pour la lutte contre les Endemies en Afrique Centrale, Yaounde, Cameroon. Mutations at five positions in the Plasmodium falciparum multidrug-resistance gene 1 (pfmdr1), initially thought to confer resistance to chloroquine, have been associated with in vitro resistance to amino alcohols and artemisinin derivatives in more recent studies. To assess the possible association between drug resistance phenotype and pfmdrl polymorphisms and establish the baseline pfmdr1 sequence data in Yaounde, Cameroon, the in vitro drug sensitivity pattern was determined for 64 clinical isolates by isotopic microtest. The pfmdr1 alleles were determined by a polymerase chain reaction and automatic sequencing. A large majority of isolates carried Tyr-86 (88%) and Phe-184 (91%) alleles. With the exception of one isolate with mixed codon 1246, all isolates had wild-type alleles Ser-1034, Asn-1042, and Asp-1246. There was no statistical association between codons 86 and 184 and in vitro response to chloroquine, amino alcohols, and artemisinin derivatives (P > 0.05). Our data do not seem to support the hypothesis that mutations in codons 86 and 184 influence the in vitro response to these drugs. Further monitoring of both in vitro response and pfmdrl polymorphisms is required to evaluate the potential role played by other pfmdr1 alleles in the determination of drug resistance in Africa. Am J Trop Med Hyg 2002 Jun;66(6):659-60

Short report: therapeutic efficacy of chloroquine combined with primaquine against Plasmodium falciparum in northeastern Papua, Indonesia.

Baird JK, Wiady I, Sutanihardja A, Suradi, Purnomo, Basri H, Sekartuti, Ayomi E, Fryauff DJ, Hoffman SL.

US Naval Medical Research Unit No 2, American Embassy Jakarta, Indonesia. Email: [email protected]

Chloroquine combined with primaquine was evaluated for therapy of uncomplicated malaria caused by Plasmodium falciparum in nonimmune Javanese migrants to northeastern Papua, Indonesia. Subjects were randomized to treatment with standard chloroquine therapy (25 mg/kg in 3 doses over the course of 48 hours) with 30 mg primaquine administered daily for 28 days (n = 25) or a placebo of primaquine (n = 28). The 14-day cumulative incidence of therapeutic failure was 56% with primaquine and 79% with placebo (odds ratio [OR], 0.35; 95% confidence interval [CI], 0.1-1.3; P = 0.08). Primaquine administered daily created a marginally significant improvement in therapeutic efficacy at day 14, but not at day 7 (20% versus 36%; OR, 0.2; 95% CI, 0.1-1.8; P = 0.2) or day 28 (82% versus 93%; OR, 0.31; 95% Cl, 0.04-2.1; P = 0.23). This report corroborates studies suggesting that therapeutic doses of primaquine exert no discernible effect on parasitemia by P. falciparum. Am J Trop Med Hyg 2002 Jun;66(6):653-8

New emerging Plasmodium falciparum genotypes in children during the transition phase from asymptomatic parasitemia to malaria.

Kun JF, Missinou MA, Lell B, Sovric M, Knoop H, Bojowald B, Dangelmaier O, Kremsner PG. Department of Parasitology, Institute of Tropical Medicine, University of Tubingen, Germany. Email: [email protected]

Semi-immunity against Plasmodium falciparum occurs after many infections. In areas of high malaria transmission, the prevalence of asymptomatic parasite carriers increases with age. We investigated P. falciparum genotypes in a cohort of asymptomatic carriers who were followed until they became symptomatic. Blood spots on filter paper and blood smears were collected daily from 10 children in Lambarene, Gabon. The parasite genotypes present on successive days were determined by a polymerase chain reaction using the polymorphic region of the merozoite surface antigen-2 for typing. The same parasite genotypes persisted in eight out of ten children and parasite densities were low throughout the asymptomatic phase indicating inhibition of parasite growth. Appearance of symptoms was associated with an increase in parasitemia and appearance of novel parasite genotypes. The results suggest that the parasites causing a clinical episode are those against which a child has not yet mounted an efficient protective immune response. Am J Trop Med Hyg 2002 Jun;66(6):649-52

Assessing the Parasight-F test in northeastern Papua, Indonesia, an area of mixed Plasmodium falciparum and Plasmodium vivax transmission.

Taylor WR, Widjaja H, Basri H, Fryauff DJ, Ohrt C, Taufik, Tjitra E, Hoffman SL, Baso S, Richie TL. US

Naval Medical Research Unit No 2, Jakarta, Indonesia. Email: [email protected]

User-friendly, reliable, and inexpensive methods for diagnosing malaria are needed at the primary health care level. During a randomized treatment trial, the Parasight-F test was assessed on days 0, 3, 7, and 28 against standard light microscopy of Giemsa-stained thick blood smears for diagnosing Plasmodium falciparum parasitemia in patients with P. falciparum (n = 84) or P. vivax (n = 59) malaria. The median P. falciparum parasite count on day 0 was 2,373/microL (range = 20-74,432/microL). At the start of treatment, the Parasight-F test had a sensitivity of 95.2% (80 of 84; 95% confidence interval [CI] = 88.2-98.7), and a specificity of 94.9% (56 of 59; 95% CI = 85.8-98.9). On day 7, this test showed false-positive results in 17 (16.3%) of 104 patients (95% CI = 9.8-24.9). The Parasight-F test performed well when compared with light microscopy in detecting P. falciparum parasitemia in patients presenting with clinical malaria. However, the high false-positive rate on day 7 limits its use for patient follow-up. Am J Trop Med Hyg 2002 Jun;66(6):641-8

High prevalence of asymptomatic Plasmodium vivax and Plasmodium falciparum infections in native Amazonian populations.

Alves FP, Durlacher RR, Menezes MJ, Krieger H, Silva LH, Camargo EP.

Department of Parasitology, University of Sao Paulo, Sao Paulo, Brazil. The epidemiology of malaria in 2 riverine localities in Rondjnia, Brazilian western Amazjnia, was assessed by a 1-year study at Portuchuelo, and a cross-sectional survey at riverine communities at Rio Machado (= Ji-Parana). Plasmodium spp. infections were diagnosed by light microscopy and by polymerase chain reaction (PCR) amplification of ribosomal DNA. PCR was 6-7 times more efficient than microscopy for detecting plasmodial infections. Both Plasmodium vivax and Plasmodium falciparum infections occurred as asymptomatic and symptomatic forms of the disease. The relation between symptomatic and asymptomatic clinical forms was roughly similar for both species of Plasmodium. Symptomless patients were monitored for 2 months. The prevalence of symptomless infections was 4-5 times higher than the symptomatic ones–respectively, 20% and 4.6% for Portuchuelo and 49.5% and 10% for Ji-Parana. Symptomatic malaria occurred mostly in patients in younger age groups. In contrast, there was a significant association of symptomless malaria with older age groups (medians of 26.5 and 21 years, respectively, for Portuchuelo and Ji-Parana), whereas the age medians for symptomatic malaria were 14 and 8 years, respectively, in the 2 regions. Symptomatic malaria also was more prevalent in groups living for shorter times in Amazjnia (13 and 4 years, respectively, for Portuchuelo and Ji-ParanA) as compared with symptomless malaria, which was more prevalent in groups living for longer periods in the region (medians of 25.5 and 18 years, respectively, for Portuchuelo and Ji-Parana). The high prevalence of symptomless malaria may pose new problems for the currently adopted strategy for the control of malaria in the Amazonian region, which is essentially based on the treatment of symptomatic patients. Harefuah 2002 Aug;141(8):699-701, 762, 761

[Malaria in Israel–can severe malaria related morbidity and mortality be prevented?] [Article in Hebrew] Schwartz E.

Malaria was eradicated in Israel about 50 years ago. Despite this, the number of cases of malaria in Israel has been increasing in the past few years due to imported malaria from endemic countries. Although malaria is a preventable and treatable disease, severe and fatal cases of malaria occur every year. The majority of malaria cases occur in travelers who did not take prophylaxis. Therefore, there is a tendency to blame them for their severe disease. However, malaria morbidity and mortality increases with any delay in diagnosis and treatment. Hence, it should be emphasized, that there are three links to this chain: the patient who did not take malaria prophylaxis, the physician who failed to consider malaria as the diagnosis of a febrile patient who had just returned from an endemic area, and finally, the hospitals that usually do not store anti-malarial medication. Action should therefore be taken on three levels: first and most easily remedied–hospitals should have anti-malarial medication available by law. Second are the physicians who must be educated with regard to the risk of malaria in returning travelers, and methods of diagnosis. Thirdly, efforts must continue to increase compliance of malaria prophylaxis among travelers to endemic areas. FEBS Lett 2002 Sep 11;527(1-3):95

Protection against experimental malaria associated with AMA-1 peptide analogue structures.

Salazar L, Alba M, Torres M, Pinto M, Cortes X, Torres L, Patarroyo M.

Fundacion Instituto de Inmunologi;a de Colombia (FIDIC), Universidad Nacional de Colombia, Carrera 50 No. 26-00, Bogota, Colombia.

One Plasmodium falciparum malaria antigen is an integral membrane protein called apical membrane antigen-1. High activity binding peptides to human red blood cells have been identified in this protein. 4337 is a conserved, non-immunogenic peptide with high activity red blood cell binding and its critical residues have already been identified. Peptide analogues (with amino acids having the same mass but different charge) were generated to change their immunogenic and protective characteristics. Three analogues having positive or negative immunological results were studied by nuclear magnetic resonance. The studied peptides all had an alpha-helix fragment, but in different peptide regions and extensions, except for randomly structured 4337. We show that altering a few amino acids induced immunogenicity and protectivity against experimental malaria and changed their three-dimensional structure, suggesting a better fit with immune system molecules and that modified peptides having better immunological properties can be included in the design of new malaria multi-component subunit-based vaccine. Lancet Infect Dis 2002 Sep;2(9):564

Malaria: current status of control, diagnosis, treatment, and a proposed agenda for research and development.

Guerin P, Olliaro P, Nosten F, Druilhe P, Laxminarayan R, Binka F, Kilama W, Ford N, White N. PJG is an EPITET fellow of the Norwegian Institute of Public Health and was formerly at Epicentre, Paris, France

Rolling back malaria is possible. Tools are available but they are not used. Several countries deploy, as their national malaria control treatment policy, drugs that are no longer effective. New and innovative methods of vector control, diagnosis, and treatment should be developed, and work towards development of new drugs and a vaccine should receive much greater support. But the pressing need, in the face of increasing global mortality and general lack of progress in malaria control, is research into the best methods of deploying and using existing approaches, particularly insecticide-treated mosquito nets, rapid methods of diagnosis, and artemisinin-based combination treatments. Evidence on these approaches should provide national governments and international donors with the cost-benefit information that would justify much-needed increases in global support for appropriate and effective malaria control. Mem Inst Oswaldo Cruz 2002 Jul;97(5):731-5

Performance of OptiMAL(R) in the diagnosis of Plasmodium vivax and Plasmodium falciparum infections in a malaria referral center in Colombia.

Ferro BE, Gonzalez IJ, Carvajal Fd F, Palma GI, Saravia NG. Centro Internacional de Entrenamiento e Investigaciones Medicas, Cali, Colombia.

Alternative, non-microscopic methods for the diagnosis of malaria have recently become available. Among these, rapid dipstick methods stand out. One such test, OptiMAL(R), is based on the immunochromatographic detection of Plasmodium lactate dehydrogenase (pLDH) and has the capacity to detect and distinguish infections caused by P. falciparum and Plasmodium sp. This capacity is particularly important in countries where different species of Plasmodium co-exist. In this study we evaluated the performance of OptiMAL(R) in an urban referral center for malaria diagnosis. Two sets of patients were included: one (n = 112) having predetermined infections with P. falciparum or P. vivax and individuals with negative blood smears; and another consisting of all eligible consecutive patients (n = 80) consulting for diagnosis at the referral center during one month. The overall diagnostic efficiency of OptiMAL(R) for both sets of patients was 96.9%. Efficiency was higher for P. vivax (98.1%) than for P. falciparum (94.9%). These results corroborate the diagnostic utility of OptiMAL(R) in settings where P. vivax and P. falciparum co-exist and support its implementation where microscopic diagnosis is unavailable and in circumstances that exceed the capacity of the local microscopic diagnosis facility. J Immunol 2002 Sep 15;169(6):2956-63 Innate Immune Response to Malaria: Rapid Induction of IFN-gamma from Human NK Cells by Live Plasmodium falciparum-Infected Erythrocytes. Artavanis-Tsakonas K, Riley EM. Department of Infectious and Tropical Diseases, London School of Hygiene and Tropical Medicine, London, United Kingdom. To determine the potential contribution of innate immune responses to the early proinflammatory cytokine response to Plasmodium falciparum malaria, we have examined the kinetics and cellular sources of IFN-gamma production in response to human PBMC activation by intact, infected RBC (iRBC) or freeze-thaw lysates of P. falciparum schizonts. Infected erythrocytes induce a more rapid and intense IFN-gamma response from malaria-naive PBMC than do P. falciparum schizont lysates correlating with rapid iRBC activation of the CD3(-)CD56(+) NK cell population to produce IFN-gamma. IFN-gamma(+) NK cells are detectable within 6 h of coculture with iRBC, their numbers peaking at 24 h in most donors. There is marked heterogeneity between donors in magnitude of the NK-IFN-gamma response that does not correlate with mitogen- or cytokine-induced NK activation or prior malaria exposure. The NK cell-mediated IFN-gamma response is highly IL-12 dependent and appears to be partially IL-18 dependent. Exogenous rIL-12 or rIL-18 did not augment NK cell IFN-gamma responses, indicating that production of IL-12 and IL-18 is not the limiting factor explaining differences in NK cell reactivity between donors or between live and dead parasites. These data indicate that NK cells may represent an important early source of IFN-gamma, a cytokine that has been implicated in induction of various antiparasitic effector mechanisms. The heterogeneity of this early IFN-gamma response between donors suggests a variation in their ability to mount a rapid proinflammatory cytokine response to malaria infection that may, in turn, influence their innate susceptibility to malaria infection, malaria-related morbidity, or death from malaria. J Emerg Med 2002 May;23(1):23

Malaria: a rising incidence in the United States.

Jerrard D, Broder J, Hanna J, Colletti J, Grundmann K, Geroff A, Mattu A.

University of Maryland School of Medicine, Baltimore, Maryland, USA.

Malaria is frequently a deadly disease, particularly in tropical countries of the world where this protozoan infection is endemic. While physicians in tropical countries are familiar with the presentation, those who do not practice in endemic regions of the world may neglect to add tropical diseases to their differential diagnosis of fever. Epidemiologic data from the CDC show the number of cases of malaria being diagnosed in the United States in the last decade has risen sharply. With international travel continuing to rise, there is strong reason to consider malaria as a source of fever. Peptides 2002 Sep;23(9):1527

Characterization of antimalarial SPf66 peptide using MALDI-TOF MS, CD and SEC.

Oliva A, Dorta M, Santovena A, Bonetto V, Salmona M, Farina J. Dpto.

Ingenieri;a Qui;mica y Tecnologi;a Farmaceutica, Facultad de Farmacia, Universidad de La Laguna, 38200 La Laguna, Tenerife, Spain.

SPf66 is the first chemically synthesized peptide to elicit a partial protective immune response against malaria. Size-exclusion chromatography (SEC) with multi-angle laser light-scattering (MALLS) detection and hydrogen/deuterium (H/D) exchange monitored by (matrix-assisted laser desorption/ionization) MALDI-TOF (time-of-flight) mass spectrometry (MS) were used to assess the conformation and stability in aqueous solution after storage at different temperatures. Moreover, the feasible conformational changes of this peptide were also measured by circular dichroism (CD)-spectroscopy. The absolute molecular weight of SPf66 monomer and dimer species were 4765 and 8960Da using SEC with MALLS detection, and 4643 and 9490Da by MALDI-TOF MS, the discrepancy being between both methods lower than 5.7%, a value quite close to those found in other proteins. The results from H/D exchange monitored by MALDI-TOF MS and CD-spectroscopy show that the SPf66 monomer lacks ordered structure, whereas the SPf66 dimer species presents segments of secondary structure as a determined by CD measurements. J Egypt Soc Parasitol 2002 Aug;32(2):611-23

The efficacy of artemether versus quinine in the treatment of cerebral malaria.

Satti GM, Elhassan SH, Ibrahim SA. Department of Biochemistry, Faculty of Medicine, University of Khartoum, Sudan.

Cerebral malaria remains a major cause of childhood morbidity. Quinine is the drug of choice for which resistance is now emerging. A total of 77 children admitted to Khartoum Children Emergency Hospital who conform to WHO criteria of cerebral malaria were randomly allocated to receive either artemether (1.6 mg/kg body wt., repeated after 12 hrs and then daily for four days) or quinine (10 mg/kg body wt in 10 ml/kg body wt of 5% dextrose in 0.9% saline intravenously. Repeated every 8 hrs and changed to oral administration when the child was able to drink to finish seven days). Response to therapy was evaluated using fever clearance time (FCT), time of regaining consciousness (TRC) and parasite clearance time (PCT). The FCT (mean+SD), TRC and PCT for the artemether-treated group were 32 (+13) hrs, 21 (+11) hrs and 36 (+18) hrs, respectively, while for the quinine-treated group the respective figures were 36 (+18), 26 (+15) hrs and 41 (+12) hrs. The response to artemether was slightly better than that of quinine, but the differences between the two groups were not statistically significant. The outcome in terms of cure rate, neurological sequalae and case fatality was also comparable. J Egypt Soc Parasitol 2002 Aug;32(2):525-35

Correlation of plasma levels of tumor necrosis factor, interleukin-6 and nitric oxide with the severity of human malaria.

el-Nashar TM, el-Kholy HM, el-Shiety AG, Al-Zahaby AA. Department of Parasitology, Faculty of Medicine, Al-Azhar University, Cairo, Egypt.

Thirty two patients of malaria (15, 11 & 6) having P. vivax, uncomplicated and complicated P. falciparum malaria respectively, and 10 healthy controls were subjected to full clinical and laboratory examinations as well as estimation of plasma levels of tumor necrosis factor (TNF), interleukin-6 (IL-6) and nitric oxide (NO). The main clinical presentations were fever, pallor, jaundice, splenomegaly and anaemia which were more pronounced in patients with complicated falciparum malaria. Light coma (50%), convulsions (33.3%), severe anaemia (66.6%). severe hypoglycemia (66.6%) and increased blood lactate levels (50%) were detected in patients with complicated falciparum malaria. The results showed significant elevation of plasma levels of TNF, IL-6 and No in all malaria patients as compared to the controls. The levels were significantly higher in patients with complicated falciparum malaria than in the other patient groups. The TNF, IL-6 and No had an effective role in pathogenesis of malaria and their levels in can be a useful diagnostic markers for malaria and severity. Insect Biochem Mol Biol 2002 Sep;32(9):1171

Characterization of four Toll related genes during development and immune responses in Anopheles gambiae.

Luna C, Wang X, Huang Y, Zhang J, Zheng L.

Department of Epidemiology and Public Health, Yale University School of Medicine, CT 06520, New Haven, USA.

Toll-like receptors (TLRs) are a group of evolutionary conserved proteins with diverse biological functions. In Drosophila melanogaster, Toll protein plays an important role in pattern formation in embryogenesis and in antimicrobial immunity in larvae and adults. In insects, Toll and two other related proteins, Tehao and 18-wheeler have been shown to participate in the activation of the innate immune responses to fungal and bacterial pathogens. In this paper we report the cloning and characterization of four TLR gene from malaria vector mosquito Anopheles gambiae, AgToll, AgToll6, AgTrex, and AgToll9, orthologues of DmToll, DmToll6, DmTollo (Toll8) and DmToll9 (CG5528) in Drosophila melanogaster. The expression profiles of these genes during development, in different adult tissues and after immune challenge were examined. As expected for the orthologue of Drosophila Toll, AgToll was found to be expressed highly in the ovary and may play a role in pattern formation during embryogenesis. AgToll9, surprisingly, was found to be highly expressed in the adult gut. The potential roles of these genes in development and immunity were discussed. Parasitology 2002 Aug;125(Pt 2):93-8

Reduced efficacy of the immune melanization response in mosquitoes infected by malaria parasites.

Boete C, Paul RE, Koella JC. Laboratoire de Parasitologie Evolutive, CNRS UMR 7103, Universite P. & M. Curie, Paris, France. Email: [email protected]

Although the mosquito vectors of malaria have an effective immune system capable of encapsulating many foreign particles, they rarely encapsulate malaria parasites in natural populations. A possible reason for this apparent paradox is that infection by malaria reduces the capability of the mosquito to mount an effective immune response. To investigate this possibility, we blood-fed Aedes aegypti mosquitoes on an uninfected chicken or on one infected with Plasmodium gallinaceum, and compared the proportions of the infected and uninfected mosquitoes that melanized a negatively charged Sephadex bead injected into the thorax 1, 2 and 4 days after blood-feeding. About 40% of the uninfected mosquitoes, but less than 25% of the infected ones, melanized the bead. The difference between infected and uninfected mosquitoes was most obvious 1 day after infection (at the parasite’s ookinete stage), while the difference diminished during the early oocyst stage (2 days after infection) and disappeared at the later oocyst stage (4 days after infection). These results suggest that the parasite can either actively suppress its vector’s immune response or that it modifies the blood of its chicken host in away that reduces the efficacy of the mosquito’s immune system. In either case, the reduction of immunocompetence can have important consequences for malaria control, in particular for the current effort being invested into the genetic manipulation of mosquitoes. Epidemiol Infect 2002 Aug;129(1):85-91

Prevalence of antibodies to Brucella spp. and risk factors related to high-risk occupational groups in Eritrea.

Omer MK, Assefaw T, Skjerve E, Tekleghiorghis T, Woldehiwet Z. College of Agriculture, University of Asmara, Eritrea.

In a study of three high-risk occupational groups using Rose Bengal and complement fixation tests, the highest prevalence (7.1%) was found among dairy farm workers and owners in randomly selected dairy-cattle farms, followed by veterinary personnel (4.5%) and inhabitants in pastoralist areas (3.0%). There was no evidence for significant differences between the three populations. Among dairy farm workers, a higher risk was associated with the presence of sheep in the farm (OR = 13.2, CI = 2.2-76.7). In the pastoral area, a high risk was linked to having close contact with animals (OR = 6.32, CI = 0.88-infinity), while a reduced risk was seen for contact with cattle (OR = 0.18, CI = 0-1.30). Symptoms suggestive of brucellosis were more commonly observed among the dairy farm workers, mainly found in the highlands, than among the pastoralist area inhabitants, where malaria is prevalent. The study documents not only the presence of serological and clinical evidence of human brucellosis, but also risk factors related to it in Eritrea, for the first time. Epidemiol Infect 2002 Aug;129(1):139-45

Inter-test reliability of the anti-RESA indices based on ELISA tests using eluates from whole blood spots dried on filter paper.

Duarte EC, Gyorkos TW, Pang L, Avila S, Fontes CJ. Fundacao Nacional de Saude-FUNASA-MT, Ministry of Health, Brazil.

The ring-infected erythrocyte surface antigen (RESA), is one of the falciparum malaria vaccine candidates rarely studied in Brazil. Fieldwork logistics to conduct serology studies is simplified when eluates from whole blood dried on filter paper can be used. Therefore, this study aimed to assess the inter-test reliability for the anti-RESA ELISA-based indices using eluates from filter paper and from serum samples. The study population consisted of 210 individuals (Brazil) from whom matched samples were collected. Anti-RESA ELISA-based index means (+/- S.D.) were 15.29% (+/-28.13%) for filter paper and 11.79% (+/-23.67%) for serum samples. The intra-class correlation coefficient was estimated to be 82.38%, indicating high test reliability. However, there was a significant tendency for filter paper test results to have higher values than serum sample test results (P < 0.001). Explanations for this finding may be the presence of haemoglobin in the eluates from filter paper, which may interfere with ELISA testing. Eur J Immunol 2002 Aug;32(8):2274-81 Systemic immune responses induced by mucosal administration of lipopeptides without adjuvant. BenMohamed L, Belkaid Y, Loing E, Brahimi K, Gras-Masse H, Druilhe P. Biomedical Parasitology Unit, Pasteur Institute, Paris, France. We recently reported that parenteral injection of malaria palmitoyl-tailed peptides without adjuvant efficiently induces B, Th and CTL responses. We now show that intranasal (IN) or sub-lingual (SL) delivery of such lipopeptides induces strong systemic immune responses, as demonstrated by specific Th cell responses from the spleen as well as inguinal lymph nodes, and by the production ofhigh levels of serum antibodies. Overall, both types of responses were significantly higher than in parallel experiments in which the same lipopeptides were delivered by the subcutaneous (s.c.) route. Moreover, the mucosal route resulted in the preferential induction of IFN-gamma producing T cells and of IgG2a antibody production, as compared to the dominant IL-4 and IgG1 responses obtained by the s.c. route, thus bringing a distinct advantage in the field of many infectious diseases and allergy. Possibly related to this Th1 response, we found that dendritic cells, the principal immune-competent cells to encounter antigens within mucosal membranes, take up lipopeptide antigens more efficiently than macrophages. Mucosal immunization by lipidated peptides appears therefore as a novel, noninvasive vaccine approach that does not require the use of extraneous adjuvant and which, besides cost-effectiveness, has attractive practical and immunological features. FEMS Immunol Med Microbiol 2002 Sep 6;34(1):33

Immunogenicity and protective efficacy of three DNA vaccines encoding pre-erythrocytic- and erythrocytic-stage antigens of Plasmodium cynomolgi in rhesus monkeys.

Bhardwaj D, Hora B, Singh N, Puri S, Lalitha P, Rupa P, Chauhan V.

Malaria Research Group, International Centre for Genetic Engineering and Biotechnology, 110067, New Delhi, India.

Although several malaria vaccine candidate antigens have been identified, the most suitable methods for their delivery are still being investigated. In this regard, direct immunization with DNA encoding these vaccine target antigens is an attractive alternative. Here, we have investigated the immune responses to DNA immunization with three major vaccine target antigens: the apical membrane antigen-1 and the 19-kDa C-terminal fragment of merozoite surface protein-1 from the erythrocytic stage, and the thrombospondin-related adhesive protein from the pre-erythrocytic stage of Plasmodium cynomolgi in rhesus monkeys. Antigen-specific antibodies were developed in all the immunized monkeys and peripheral blood mononuclear cells from all immunized monkeys proliferated to different extents upon in vitro stimulation with the corresponding recombinant proteins. The immunized monkeys were challenged with P. cynomolgi sporozoites. All of the immunized animals developed infection but although there was no significant difference between the control and vaccinated animals in terms of pre-patent period, total duration of patency and primary peak parasitemia, the vaccinated animals had significantly lower secondary peak parasitemia than the control animals. Microvasc Res 2002 Sep;64(2):247

Feasibility of LDF Measurements of Optic Nerve Head Blood Flow in Children with Cerebral Malaria.

Movaffaghy A, Lochhead J, Riva C, Harding S, Petrig B, Molyneux M, Taylor T. Institut de Recherche en Ophtalmologie, Sion, Switzerland.

The pathogenesis of cerebral malaria (CM), a significant cause of death in the tropics, is still not understood. Cerebral blood flow measurements would be important but are difficult under the conditions prevailing in CM clinics in the tropics. With the goal of using optic nerve head (ONH) blood flow (F(onh)) instead of cerebral blood flow to help outcome prediction, we have tested the feasibility of performing F(onh) measurements in comatose CM children, using a portable ocular laser Doppler flowmeter (LDF). Measurements were performed in one eye of each of 13 children (2.7 +/- 1.1 years) during a period of about 8 min. The Vel(onh) (the relative blood velocity), Vol(onh) (the relative blood volume), and F(onh) values were determined for each child from three to five measurements of 2 to 20 s. Average Vel(onh), Vol(onh), and F(onh) values were 0.49 +/- 0.08 kHz, 2.4 +/- 1.06 arbitrary units (a.u.), and 89 +/- 16.8 a.u., respectively. The average coefficients of variation of the flow parameters based on all segments in each child were 13 +/- 9% (range 1-29%) for Vel(onh), 27 +/- 13% (range 3-65%) for Vol(onh), and 23 +/- 12% (range 5-42%) for F(onh). This study demonstrates the feasibility of LDF measurements in CM children. The large range of these coefficients of variations could be due to the presence of fluctuations of ONH blood flow on a short time scale in these neurologically unstable children. Acta Trop 2002 Sep;83(3):195 Plasma and in vitro levels of cytokines during and after a Plasmodium falciparum malaria attack in Gabon. Aubouy A, Deloron P, Migot-Nabias F. Centre International de Recherches Medicales de Franceville, Unite de Parasitologie Medicale, BP 769, Franceville, Gabon Fifty subjects living in a malaria endemic area were studied at diagnosis of a Plasmodium falciparum attack and 3 weeks later. Absolute numbers of CD3(+), CD4(+) and CD8(+) lymphocytes as well as plasma cytokines and secreted cytokines after in vitro mitogenic stimulation were measured. At enrolment, lymphopenia was observed, lending support to the reallocation hypothesis during the acute phase. A significant elevation of the number of CD8(+) cells was present in the peripheral blood during the recovery phase. During the acute phase, plasma IL-6 levels peaked while in vitro production capacity was high at both phases. Plasma IL-6 concentrations were positively related to blood parasite density at D0, as IL-4 and IFN-gamma, suggesting an early intervention of these cytokines. Plasma IL-2 levels were low at diagnosis although cells retained their ability to produce IL-2, which was found more frequently in plasma after cure. Acquisition of immunity with age was in relation with greater secretion abilities of cells for type1 and type 2 cytokines during the parasite clearance phase. We conclude to an early implication of type 2 cytokines and IFN-gamma, with particularly high levels of IL-6.

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