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EHP Library Malaria Bulletin No. 34: March 29-April 11, 2002
The Third MIM Pan-African Malaria Conference November 18-22, 2002 Arusha,Tanzania
REMINDER: Abstracts Submission Deadline May 1, 2002
The Secretariat of the Multilateral Initiative on Malaria (MIM) invites you to attend the Third MIM Pan-African Malaria Conference, to be held November 18-22, 2002, in Arusha, Tanzania. The MIM Pan-African Conference will focus on scientific progress and potential in malaria research with the aim of promoting the exchange of scientific ideas. The diversity of participants will provide a global perspective on scientific solutions for effectively preventing malaria and reducing its burden. The scientific program of the Conference is arranged around the following five central themes:
1. Drugs and Drug Resistance
2. Pathogenesis of Malaria and its Clinical Implications
3. Vaccine Development
4. Vector Control
5. Cross-Cutting Issues
The Conference is being organized by the MIM Secretariat, led by the FogartyInternational Center (FIC) of the U.S. National Institutes of Health, on behalf of the MIM partners and in close collaboration with Tanzania's National Institute for Medical Research (NIMR).
The deadline for abstract submission is fast approaching and I would like toencourage you to submit your abstracts soon. Abstracts, submitted in English or in French, must be text only, limited to 250 words, and only submitted once. No charts, graphs, or other figures should be included in the abstract. Abstracts should be submitted in Times New Roman 11. Abstracts should be appropriate for one of the following 5 scientific themes: Drugs and Drugs Resistance, Pathogenesis of Malaria and its Clinical Implications, Vaccine Development, Vector Control, or Cross-Cutting Issues. If you willnot be able to submit your abstract online then please contact:
MIM Malaria Conference
2025 M Street NW, Suite 800
Washington, DC 20036, USA
E-mail: [email protected]
MIM will sponsor the participation of half of the Conference attendees from malaria-endemic countries based on a critique of submitted abstracts.
Priority will be given to scientists from Africa, and malaria-endemic countries in Asia, Latin America and the Caribbean. A sponsored participant must be a presenting author of an accepted abstract (oral or poster). If you plan to apply for sponsorship or make oral or poster presentation at the conference you must submit your abstract by May 1, 2002. Sponsored participants will be contacted between June 1 and August 1, 2002, to begin all travel and logistical arrangements. DO NOT register or submit aregistration fee prior to August 1 if you are applying for sponsorship, We have also sent out the Call for Abstracts booklet with more information on the Conference. The Call for Abstracts booklet is also available on the MIM web site in the Conference section.For more information go to the updated conference section of the MIM website: http://mim.nih.gov
We look forward to seeing you in Arusha!
Martin Sarikiael Alilio, PhD
Social Sciences and Malaria
The QAP report on the work done in Bungoma with vendors is now available online. Report title: Vendor-to-vendor education to improve malaria treatment by drug outlets in Kenya. Click on http://www.qaproject.org Then on the left hand menu item: "What's New" Then on "New Products" It is found under the "Operations Research Results" section.
Indian J Public Health 2001 Jul-Sep;45(3):93-8
factors associated with malaria in a tribal area of Orissa,
Trans R Soc Trop Med Hyg 2002 Jan-Feb;96(1):85-90
comparison of chloroquine and sulfadoxine-pyrimethamine as
first-line treatment for malaria in South Africa: development of
a model for estimating recurrent direct costs.
The relative cost-effectiveness of chloroquine (CQ) and sulfadoxine-pyrimethamine (SP) as first-line antimalarial therapy in southern Africa is of great interest to policymakers, clinicians and researchers in the subregion. A model was developed to access the cost-effectiveness of replacing CQ with SP as first-line treatment in Mpumalanga, South Africa, where malaria is seasonal and the population is non-immune. In-vivo drug resistance levels were used to derive a 'resistance variable' for each drug, which was used to compare the costs to the public healthcare provider associated with either therapeutic option. Costs including drugs, staff time, transport, maintenance, utilities, training and consumables were determined and subjected to Monte Carlo simulation and subsequent analysis to generate an average cost-effectiveness ratio (ACER) with confidence intervals for each drug. SP was found to be 4.8 (95% CI 3.3-6.7) times more cost-effective than CQ in Mpumalanga at 1997 resistance levels and costs, despite the far greater cost per treatment course of SP (US$ 4.02 as opposed to US$ 0.22 for CQ) in South Africa. At the price of SP in Kenya and Uganda (US$ 0.47-4.80 per treatment course), the ACER for SP does not change materially, increasing to between 5.1 and 5.6. Resistance emerged as the factor that most influenced the ACER of a specific drug. Indirect costs, compliance, changes in effectiveness and costs over time and costs of adverse events were not included in the model owing to paucity of data and logistical difficulties. Since most of these are likely to be similar in both drug models, the relative ACER is unlikely to be significantly altered by their inclusion.
Trans R Soc Trop Med Hyg 2002 Jan-Feb;96(1):37-8
Mosquito nets for
Nine-year follow-up (ending 1999) of survival of 3738 individuals in a malaria-endemic area of Papua New Guinea found that the use of mosquito nets was associated with a large reduction in mortality in people aged > or = 40 years as well as in children aged < 5 years. There may be substantial benefits of malaria transmission reduction for older people, that have been overlooked in public health programmes and burden of disease calculations.
Clin Microbiol Rev 2002 Apr;15(2):278-93
to malaria control.
PUBMEDClin Infect Dis 2002 May 1;34(9):1192-8
as an Adjunct Therapy in Severe Plasmodium falciparum Malaria: A
The efficacy of exchange transfusion as an adjunct treatment for severe falciparum malaria is controversial. No sufficiently powered, randomized, controlled study has been reported. We analyzed 8 studies that compared survival rates associated with adjunct exchange transfusion with those associated with antimalarial chemotherapy alone. Exchange transfusion was not associated with a higher survival rate than was antimalarial chemotherapy alone (odds ratio [OR], 1.2; 95% confidence interval [CI], 0.7-2.1). However, patients who received transfusions had higher levels of parasitemia and more-severe malaria. Sensitivity analysis found that survival rates were higher among patients with partial immunity to malaria (OR, 0.5; 95% CI, 0.2-1.2) than they were among patients with no immunity (OR, 2.1; 95% CI, 0.9-4.8; P=.007). Exchange transfusion does not appear to increase the survival rate; however, there were significant problems with the comparability of treatment groups in the studies reviewed, and a randomized controlled trial is necessary to determine whether exchange transfusion is beneficial.
J Biol Chem 2002 Apr 5; Full-text: http://www.jbc.org
of dermaseptin S4 aminoheptanoyl derivative with
intraerythrocytic malaria parasite leading to increased specific
antiparasitic activity in culture.
Lancet Infect Dis 2002 Apr;2(4):209-18
Parasitol Res 2002 Feb;88(2):165-71
Synergistic in vitro
antimalarial activity of plant extracts used as traditional
herbal remedies in Mali.
Parasitol Res 2002 Feb;88(2):113-7
plasmodium falciparum proteins by mannan-binding lectin, a
component of the human innate immune system.
J Med Entomol 2002 Jan;39(1):84-8
plasmodium falciparum and C-25 sephadex beads by field-caught
Anopheles gambiae (Diptera: Culicidae) from southern Tanzania.
J Med Entomol 2002 Jan;39(1):244-7
anopheline mosquitoes (Diptera: Culicidae) from the republic of
Korea for Plasmodium vivax circumsporozoite protein.
As part of an on-going malaria surveillance effort conducted by the U.S. Forces Korea, Republic of Korea (ROK), a total of 28,286 anopheline mosquitoes was tested for the presence of Plasmodium vivax circumsporozoite (CS) protein. Mosquitoes were collected (using a variety of light and baited traps) from 29 locations throughout the ROK (the majority were collected near the de-militarized zone), identified to species, and tested by enzyme-linked immunosorbent assay for the presence of P. vivax 210 and P. vivax 247 CS protein. Recent evidence suggests that characters used to separate Anopheles sinensis Wiedemann from An. lesteri Baisas & Hu are unreliable; therefore, the data have been analyzed by grouping these two species. A total of 25,365 Anopheles sinensis/lesteri, 2,890 An. yatsushiroensis Miyazaki, and 31 An. sineroides Yamada was tested. Of these, one pool of 10 An. sinensis/lesteri collected on 9 September 1999 at Camp Howze and one pool of nine An. sinensis/ lesteri collected on 13 September 1999 at Camp Bonifas were positive for P. vivax 247.
J Med Entomol 2002 Jan;39(1):207-14
against the mosquito Anopheles stephensi (Diptera: Culicidae):
effects of cell fraction antigens on survival, fecundity, and
plasmodium berghei (Eucoccidiida: Plasmodiidae) transmission.
J Med Entomol 2002 Jan;39(1):146-51
the mosquitoes Anopheles minimus, An. sinensis, and An. saperoi
(Diptera: Culicidae) from the Ryukyu Archipelago, Japan, to the
rodent malaria Plasmodium yoelii nigeriense.
J Med Entomol 2002 Mar;39(2):350-5
transmission intensity in a village close to Yaounde, the
capital city of Cameroon.
J Med Entomol 2002 Mar;39(2):324-30
Evaluation of a
dipstick malaria sporozoite panel assay for detection of
naturally infected mosquitoes.
The determination of the presence or absence of malaria sporozoites in wild-caught Anopheles mosquitoes remains an integral component to the understanding of the transmission dynamics in endemic areas. To improve that capability, there has been on-going development of a new device using dipstick immunochromatographic technology for simplifying the testing procedure and reducing the time required to obtain results. As part of a larger multi-center effort, we evaluated the sensitivity and specificity of a prototype malaria sporozoite antigen panel assay (Medical Analysis Systems, Camarillo, CA) against three human Plasmodium species/polymorphs. The wicking (dipstick) assay was compared against a standard parasite antigen capture enzyme-linked immunosorbent assay (ELISA) for the detection of human circumsporozoite protein (CSP) in wild-caught mosquitoes. Over 6,800 Anopheles mosquitoes, representing 20 species collected from malaria endemic areas of Indonesia were tested either individually or in pools of up to 10 mosquitoes each. From 1,442 pooled test strip assays and ELISA formats, nine mosquito pools were found reactive for P.falciparum, P. vivax 210, or P. vivax 247 CSP. There was complete concordance between test strip results and ELISA results. Sensitivity was 100% and given some minor problems with false positives or negatives, specificity (n = 488) was 97%. Most strips judged as false positive produced very weak signals compared with negative control blank strips and paired ELISA-negative samples. The dipstick test proved technically simpler to perform and interpret than the ELISA and results were obtained within 15 min of exposure to mosquito suspension. This qualitative assay appears an attractive alternative to the CSP ELISA for detection of sporozoites in fresh or dried mosquitoes.
J Infect Dis 2002 Apr 15;185(8):1207-11
Identification of a
Conserved Plasmodium falciparum var Gene Implicated in Malaria
The Plasmodium falciparum erythrocyte membrane protein 1 (PfEMP1) family is a highly polymorphic class of variant surface antigens encoded by var genes that play an important role in malaria pathogenesis. This report describes the unexpected finding that 1 of the var genes encoding a PfEMP1 variant that binds to the host receptor chondroitin sulfate A (CSA) and is implicated in malaria in pregnancy is well conserved among P. falciparum isolates worldwide. The N-terminal domains of this PfEMP1 variant are especially highly conserved, whereas the functional CSA binding domain is more variable. Analysis of var gene expression in placental parasites from primigravid women in Malawi did not support a role for this conserved gene in placental infection but identified a second commonly occurring var gene. These results indicate the need for reevaluation of previous assumptions of a minimal overlap between var gene repertoires from different parasite isolates.
J Infect Dis 2002 Apr 15;185(8):1155-64
Protection of Humans
against Malaria by Immunization with Radiation-Attenuated
Plasmodium falciparum Sporozoites.
During 1989-1999, 11 volunteers were immunized by the bites of 1001-2927 irradiated mosquitoes harboring infectious sporozoites of Plasmodium falciparum (Pf) strain NF54 or clone 3D7/NF54. Ten volunteers were first challenged by the bites of Pf-infected mosquitoes 2-9 weeks after the last immunization, and all were protected. A volunteer challenged 10 weeks after the last immunization was not protected. Five previously protected volunteers were rechallenged 23-42 weeks after a secondary immunization, and 4 were protected. Two volunteers were protected when rechallenged with a heterologous Pf strain (7G8). In total, there was protection in 24 of 26 challenges. These results expand published findings demonstrating that immunization by exposure to thousands of mosquitoes carrying radiation-attenuated Pf sporozoites is safe and well tolerated and elicits strain-transcendent protective immunity that persists for at least 42 weeks.
Blood 2002 Apr 15;99(8):2677-84
uses the murine Duffy antigen receptor for chemokines as a
receptor for normocyte invasion and an alternative receptor for
Erythrocyte invasion by malaria parasites is a complex multistep process involving parasite and erythrocyte receptors. It is a critical stage in the parasite life cycle and, therefore, a logical step in which to intervene to prevent or ameliorate disease. Rodent models of malaria, commonly Plasmodium yoelii, are frequently used for studies of malaria pathogenesis. Little is known, however, about the invasion machinery of rodent malaria parasites. We have found previously that mice congenic for a region of chromosome 1, containing the Duffy antigen/receptor for chemokines (DARC), have different susceptibility to P yoelii infection. Because P vivax, a human parasite, and P knowlesi, a simian parasite, use DARC to enter human erythrocytes, we sought to identify the role of the murine DARC in P yoelii invasion. Using a novel in vivo invasion assay and DARC knock-out mice, we found that DARC knock-out normocytes (mature erythrocytes) had negligible levels of P yoelii invasion compared with wild-type normocytes, demonstrating that DARC is a receptor for invasion of murine erythrocytes. In contrast, DARC knock-out reticulocytes were invaded at a rate similar to that for wild-type reticulocytes. We conclude that there is a DARC- independent pathway for reticulocyte invasion. These findings represent the first identification of a murine malaria receptor on erythrocytes and the first determination that different pathways of invasion exist on normocytes and reticulocytes. Because we show conservation of host-receptor interactions between rodent and human malaria, we can now use this model to identify how immunity can interfere with the invasion process.
Tissue Antigens 2001 Dec;58(6):407-10
of a tumor necrosis factor-alpha promoter allele with cerebral
malaria in Myanmar.
J Exp Med 2002 Apr 1;195(7):881-892
The Mechanism and
Significance of Deletion of Parasite-specific CD4(+) T Cells in
EMBO J 2002 Apr 1;21(7):1597-1606
sporozoite invasion into insect and mammalian cells is directed
by the same dual binding system.
Plasmodium sporozoites, the transmission form of the malaria parasite, successively invade salivary glands in the mosquito vector and the liver in the mammalian host. Sporozoite capacity to invade host cells is mechanistically related to their ability to glide on solid substrates, both activities depending on the transmembrane protein TRAP. Here, we show that loss-of- function mutations in two adhesive modules of the TRAP ectodomain, an integrin-like A-domain and a thrombospondin type I repeat, specifically decrease sporozoite invasion of host cells but do not affect sporozoite gliding and adhesion to cells. Irrespective of the target cell, i.e. in mosquitoes, rodents and cultured human or hamster cells, sporozoites bearing mutations in one module are less invasive, while those bearing mutations in both modules are non-invasive. In Chinese hamster ovary cells, the TRAP modules interact with distinct cell receptors during sporozoite invasion, and thus act as independently active pass keys. As these modules are also present in other members of the TRAP family of proteins in Apicomplexa, they may account for the capacity of these parasites to enter many cell types of phylogenetically distant origins.
Trans R Soc Trop Med Hyg 2002 Jan-Feb;96(1):70-1
falciparum parasites in clinical P. vivax blood samples from
J Biomol Struct Dyn 2002 Apr;19(5):765-74
Homology modeling of
falcipain-2: validation, de novo ligand design and synthesis of
Increasing resistance of malaria parasites, in particular Plasmodiun falciparum, demands a serious search for novel targets. Cysteine protease in P. falciparum, encoded by a previously unidentified gene falcipain 2, provides one such target to design chemotherapeutic agents for treatment of malaria. In fact, a few cysteine protease inhibitors have been shown to inhibit growth of cultured malarial parasites. In absence of a crystal structure for this enzyme, homology modeling proved to be a reasonable alternative to study binding requirements of the enzyme. A homology model for falcipain 2 was developed and validated by docking of known vinyl sulfone inhibitors. Further, based on the observations of these studies, novel isoquinoline inhibitors were designed and synthesized, which exhibited in vitro enzyme inhibition at micromolar concentrations.
Parasitology 2002 Mar;124(Pt 3):247-63
of untreated Plasmodium falciparum malaria within the adult
human host during the expansion phase of the infection.
A retrospective analysis was performed of parasite count data recorded from the first 7 days of blood or mosquito transmitted Plasmodium falciparum infections given for the treatment of neurosyphilis in the USA before 1963. The objective of this study was to characterize initial growth dynamics before host defences have significant effects on the infecting parasite population. Of the 328 patients' data available for analysis, 83 were excluded because they had received anti-malarial treatment during the first 7 days of the patent infection. Nonlinear mixed effects modelling was performed to estimate the parameters of interest; 'parasite multiplication rate per 48 h' (PMR), and length of the parasite life-cycle (periodicity). The parasitaemia versus time profiles showed great variability between patients. The mean population estimate of 'PMR' was approximately 8, and was highly dependent on the P. falciparum 'strain'. PMR also varied significantly between patients with a 90% prediction interval varying from 5.5 to 12.3-fold. Both intrinsic parasite multiplication rate (an intrinsic virulence determinant), and host susceptibility and defence contribute to expansion of the parasite biomass and thus disease severity in falciparum malaria.
Parasitology 2002 Mar;124(Pt 3):237-46
properties of the Plasmodium vivax vaccine candidate MSP1(19)
expressed as a secreted non-glycosylated polypeptide from Pichia
The 19 kDa C-terminal region of the merozoite surface protein 1 (MSP1(19)) is one of the most promising vaccine candidates against the erythrocytic forms of malaria. In the present study, a gene encoding the Plasmodium vivax MSP1(19) epitope (PvMSP1(19)) and the Pan-Allelic DR epitope (PADRE) was expressed in the methylotrophic yeast Pichia pastoris. A non-glycosylated form of the recombinant protein rPvMSP1(19)-PADRE was purified from culture supernatants. This recombinant protein maintains its antigenicity, being recognized by a very high percentage (85.6%) of sera from Brazilian individuals naturally exposed to P. vivax. The antibody immune response elicited by rPvMSP1(19)-PADRE was compared in C57BL/6 mice immunized with different adjuvant formulations. After 3 immunizing doses, antibody titres induced in the presence of the adjuvants monophosphoryl lipid A, trehalose dicorynomycolate and cell wall skeleton or alum plus CpG ODN 1826 were as high as titres generated by Complete Freund's Adjuvant. Based on these immunological studies, we concluded that rPvMSP1(19)-PADRE deserves further evaluation in pre-clinical immunizations against P. vivax in non-human primates.
Parasitology 2002 Mar;124(Pt 3):225-35
falciparum var gene switching rate, switching mechanism and
patterns of parasite recrudescence described by mathematical
Recrudescing Plasmodium falciparum parasitaemia is attributed to the switching of PfEMP1, a variant antigen family encoded by the var gene repertoire, and the host's immune response. We have developed a mathematical model which incorporates var gene switching, and variant specific, non-variant specific and non-specific immunity. By conducting a sensitivity analysis of the model we have defined the parameter limits which produce chronic and recrudescing infections. We explore 3 switching mechanisms: ordered, random and uncoupled switching. We show that if var genes switch on and off independently at variable rates through the repertoire a chronic clinical infection is predicted. The fastest switching-on rate that produces a chronic infection is 0.03% per generation. The model predicts that non-variant specific immunity plays an important role in reducing disease severity. This work illustrates the complex relationship between the malaria parasite and its host and shows that var gene switching at rates substantially slower than 2% are essential for parasite survival.
J Infect Dis 2002 Apr 1;185(7):971-9
Absolute Levels and
Ratios of Proinflammatory and Anti-inflammatory Cytokine
Production In Vitro Predict Clinical Immunity to Plasmodium
J Infect Dis 2002 Mar 15;185(6):820-7
blood-stage malaria vaccine reduces Plasmodium falciparum
density and exerts selective pressure on parasite populations in
a phase 1-2b trial in Papua New Guinea.
The malaria vaccine Combination B comprises recombinant Plasmodium falciparum ring-infected erythrocyte surface antigen and 2 merozoite surface proteins (MSP1 and MSP2) formulated in oil-based adjuvant. A phase 1-2b double-blind, randomized, placebo-controlled trial in 120 children (5-9 years old) in Papua New Guinea demonstrated a 62% (95% confidence limits: 13%, 84%) reduction in parasite density in children not pretreated with sulfadoxine-pyrimethamine. Vaccinees had a lower prevalence of parasites carrying the MSP2-3D7 allelic form (corresponding to that in the vaccine) and a higher incidence of morbid episodes associated with FC27-type parasites. These results demonstrate functional activity of Combination B against P. falciparum in individuals with previous malaria exposure. The specific effects on parasites with particular msp2 genotypes suggest that the MSP2 component, at least in part, accounted for the activity. The vaccine-induced selection pressure exerted on the parasites and its consequences for morbidity strongly argue for developing vaccines comprising conserved antigens and/or multiple components covering all important allelic types.
J Infect Dis 2002 Mar 15;185(6):812-9
CD4 T cell responses
to a variant antigen of the malaria parasite Plasmodium
falciparum, erythrocyte membrane protein-1, in individuals
living in malaria-endemic areas.
Curr Genet 2002 Mar;40(6):391-398
The genome of
Plasmodium falciparum encodes an active delta-aminolevulinic
The enzyme delta-aminolevulinic acid
dehydratase (ALAD) catalyses the second reaction in the heme
biosynthetic pathway. It has been suggested previously that the
malaria parasite Plasmodium falciparumimports this enzyme from
the host cell for de novo heme biosynthesis. However, the
parasite's genome encodes an orthologue for ALAD. Here we report
molecular cloning of a complete cDNA for the parasite's
intrinsic ALAD and show it rescues an ALAD-null mutant of
Escherichia coli, indicating that the malarial gene encodes a
functional ALAD. The malarial ALAD has a long bipartite
extension at its N-terminus, which may function as a plastid
targeting signal. The amino acid sequence of the enzyme is
related most closely to those of plant/algal chloroplast ALADs,
though the malarial version may lack the allosteric
Mg(2+)-binding site, which is conserved among chloroplast ALADs.
AIDS 2002 Apr 12;16(6):909-18
Causes and empirical
treatment of fever in HIV-infected adult outpatients, Abidjan,
Br J Haematol 2002 Apr;117(1):203-11
functional roles to parasite proteins in malaria-infected red
blood cells by competitive flow-based adhesion assay.
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Last modified April 12, 2002